Determining a characteristic of a lumen by measuring velocity of a contrast agent

ABSTRACT

Apparatus and methods are described for use with a plurality of angiographic image frames of a moving lumen of a subject, including aligning the image frames with each other. Using the aligned image frames, a time it takes a contrast agent to travel a known distance through the lumen is determined. At least partially in response thereto, a characteristic of the lumen is determined, and, in response to the determined characteristic, an output is generated on a display. Other applications are also described.

CROSS REFERENCES TO RELATED APPLICATIONS

The present application is:

(i) a continuation of PCT Application no. PCT/IL2013/050549 to Tolkowsky(published as WO 14/002095), filed Jun. 26, 2013, which claims thebenefit of:

-   -   U.S. Provisional Patent Application 61/690,393, entitled        “Flow-related image processing in luminal organs,” filed Jun.        26, 2012;    -   U.S. Provisional Patent Application 61/741,105, entitled        “Flow-related image processing in luminal organs,” filed Jul.        12, 2012;    -   U.S. Provisional Patent Application 61/692,280, entitled        “Flow-related image processing in luminal organs,” filed Aug.        23, 2012; and    -   U.S. Provisional Patent Application 61/704,570, entitled        “Flow-related image processing in luminal organs,” filed Sep.        24, 2012; and

(ii) a continuation-in-part of U.S. patent application Ser. No.12/075,244 to Tolkowsky (published as 2008/0221442, now abandoned),filed Mar. 10, 2008, entitled “Imaging for use with moving organs,”which claims the benefit of U.S. Provisional Patent Application Nos.:

-   -   60/906,091 filed on Mar. 8, 2007;    -   60/924,609 filed on May 22, 2007;    -   60/929,165 filed on Jun. 15, 2007;    -   60/935,914 filed on Sep. 6 2007; and    -   60/996,746 filed on Dec. 4, 2007,

all entitled “Apparatuses and methods for performing medical procedureson cyclically-moving body organs.”

The present application is related to the following patent applications:

-   -   International Patent Application PCT/IL2013/050438 (published as        WO 13/175472), entitled “Co-use of endoluminal data and        extraluminal imaging,” filed May 21, 2013;    -   International Patent Application PCT/IL2012/000246 (published as        WO 12/176191), entitled “Luminal background cleaning,” filed        Jun. 21, 2012;    -   International Patent Application PCT/IL2011/000612 (published as        WO 12/014212), entitled “Co-use of endoluminal data and        extraluminal imaging,” filed Jul. 28, 2011;    -   U.S. patent application Ser. No. 13/228,229 (published as US        2012/0004537), entitled “Co-use of endoluminal data and        extraluminal imaging,” filed Sep. 8, 2011;    -   International Patent Application PCT/IL2011/000391 (published as        WO 11/145094), entitled “Identification and presentation of        device-to-vessel relative motion,” filed May 17, 2011;    -   U.S. patent application Ser. No. 12/781,260 to Blank (published        as US 2010/0228076, now abandoned), entitled “Controlled        actuation and deployment of a medical device,” filed May 17,        2010;    -   U.S. patent application Ser. No. 12/650,605 to Cohen (published        as US 2010/0172556), entitled “Automatic enhancement of an image        stream of a moving organ,” filed Dec. 31, 2009;    -   International Patent Application No. PCT/IL2009/001089        (published as WO 10/058398), entitled “Image processing and tool        actuation for medical procedures,” filed Nov. 18, 2009; and

U.S. patent application Ser. No. 12/487,315 to Iddan (issued as U.S.Pat. No. 8,700,130), entitled “Stepwise advancement of a medical tool,”filed Jun. 18, 2009.

All of the aforementioned references are incorporated herein byreference.

FIELD OF EMBODIMENTS OF THE INVENTION

Some applications of the present invention generally relate to medicalimaging. Specifically, some applications of the present invention relateto determining a luminal-flow-related index, such as fractional flowreserve (FFR), based upon medical imaging.

BACKGROUND

Fractional flow reserve (FFR) is physiological index that measures thefunctional severity of a coronary artery stenosis (i.e., a narrowing,and/or an occlusion of the artery that is usually due toatherosclerosis). FFR measures the severity of the stenosis bydetermining the maximal blood flow through the artery in the presence ofthe stenosis relative to the hypothetical level of blood flow throughthe artery, if the artery were healthy. FFR provides an indication ofthe likelihood that the stenosis is impeding and/or will impede oxygendelivery to the heart muscle (i.e., the likelihood that the stenosis iscausing and/or will cause myocardial ischemia). Otherluminal-flow-related indices that are used to measure conditions of thecoronary circulatory system include instantaneous wave-free ratio (iFR),coronary flow reserve (CFR), index of microcirculatory resistance (IMR),microvascular resistance index (MVRI), TIMI myocardial perfusion grade(TMPG), relative fractional flow reserve (RFFR), and other related(e.g., other statistically correlated) indices.

FFR is typically utilized in coronary catheterizations, and is typicallycalculated by measuring pressure differences across a coronary arterystenosis. Assuming that there is single stenosis, the relationshipbetween the pressure downstream of the stenosis and the pressureupstream of the stenosis approximates the relationship between the flowof blood in the currently-stenosed coronary artery and the normal flowof blood had the artery been healthy. Thus, measuring pressuredifferences across a coronary artery stenosis provides an approximationof the FFR.

Typically, FFR serves as a decision support tool for determining whetherthe stenosis should be treated, such as by means of inflating a balloonand implanting a stent.

FFR is defined as the ratio between stenotic flow Q_(S) and normal flowQ_(N) under hyperemic conditions:FFR=Q _(S) /Q _(N)

Using the flow equation Q=ΔP/R, where Q is the flow (mL/min), ΔP is thepressure difference (mm Hg), and R is resistance (mmHg×min/mL), and theassumption that the venous pressure P_(vein) is negligible, the FFR canbe expressed as the ratio between distal pressure Pd to proximalpressure Pa of a stenosis:FFR=(Q _(S) /Q _(N))=((P _(d) −P _(vein))/R)/((P _(a) −P _(vein))/R)=P_(d) /P _(a)

This pressure ratio can be written as follows:FFR=P _(d) /P _(a)=(P _(a) −ΔP _(s))/P _(a)

where ΔP_(s) is the pressure drop along the axis of the lumen along asegment of the lumen from upstream of the stenosis to downstream of thestenosis.

The FFR result is an absolute number between zero and one; an FFR of0.50 means that a given stenosis causes a 50% drop in blood pressure. Inother words, FFR expresses the maximal flow through a lumen in thepresence of a stenosis compared to the maximal flow in the hypotheticalabsence of the stenosis.

Typically, FFR is measured in coronary vessels by means of insertinginto such vessels a wire equipped with sensors. The device analyzespressure and flow parameters from inside of the vessel. Such wires arecurrently being produced by Volcano Corp. (San Diego, Calif.) and by St.Jude Medical (St. Paul, Minn.).

SUMMARY OF EMBODIMENTS

For some applications of the present invention, flow-related imageprocessing is performed on luminal organs. Typically, a set ofangiographic images of a lumen is acquired, and the geometry of thelumen at a given location within the lumen (typically, in a vicinity ofa stenosis within the lumen) is determined automatically by performingimage processing on at least one of the angiographic images. Bloodvelocity along the lumen is determined automatically, by performingimage processing on at least two of the angiographic images. Typically,the geometry of the lumen and the blood velocity are determined withoutgenerating a three dimensional model of the lumen. For someapplications, the geometry of the lumen and the blood velocity aredetermined solely by performing image-processing on two-dimensionalangiographic images of the lumen. Based upon the geometry of the lumenand the blood velocity, the value of a current flow-related parameter ofthe lumen at the given location is determined. For example, the currentflow, blood pressure, and/or blood velocity may be determined. Anindication of a value of a second flow-related parameter of the subjectis received. For example, an indication of blood pressure at an upstreamlocation (e.g., aortic pressure) may be received. Alternatively oradditionally, a historic angiographic image sequence that was acquiredwhen the lumen was healthy may be received, and flow, blood pressure,and/or blood velocity within the lumen at the time when the lumen washealthy may be derived from the historic angiographic image sequence. Avalue of a luminal-flow-related index of the subject (such as the FFR ofthe subject) at the location is determined by determining a relationshipbetween the value of the current flow-related parameter and the value ofthe second flow-related parameter.

For some applications, the value of a luminal-flow-related index of thesubject is determined by (a) automatically determining pressure at asite based upon the automatically-determined lumen geometry and theautomatically-determined blood velocity at the site, and (b) determininga relationship between the automatically-determined pressure at thesite, and the subject's aortic pressure. An output is typicallygenerated in response to the determined index at the site. For example,a stabilized image stream that is based upon the acquired angiographicimages may be displayed, and, at a location within the image streamcorresponding to the site, an indication of the index at the site may bedisplayed. For some applications, an indication of the value of theflow-related index is generated on an image of the lumen, using a colorlegend. Alternatively or additionally, in response to theluminal-flow-related index passing a first threshold value, an output isgenerated indicating that treatment of the subject is recommended, andin response to the luminal-flow-related index passing a second thresholdvalue but not passing the first threshold value, an output is generatedrecommending that the luminal-flow-related index be measured using asensor that is inserted into the lumen.

Typically, image processing described in the present application isperformed intra-procedurally, though, for some applications, imageprocessing is applied post-procedurally.

Although some applications of the present invention are described withreference to coronary catheterizations, the scope of the presentinvention includes applying the apparatus and methods described hereinto other medical procedures and to other luminal organs in which thereis a flow of fluid. For example, for some applications, the apparatusand methods described herein are applied, mutatis mutandis, to renalcatheterization procedures, subclavian procedures, and/or below-the-kneeprocedures. For some such applications, determining aluminal-flow-related index using angiographic data facilitatesdetermination of such an index, even in cases in which determination ofthe index via insertion of a wire would be physiologically difficult.

Although some applications of the present invention are described withreference to determining a subject's fractional flow reserve, the scopeof the present invention includes applying the apparatus and methodsdescribed herein to determine other luminal-flow-related indices,including but not limited to instantaneous wave-free ratio (iFR),coronary flow reserve (CFR), index of microcirculatory resistance (IMR),microvascular resistance index (MVRI), TIMI myocardial perfusion grade(TMPG), relative fractional flow reserve (RFFR), and/or other related(e.g., other statistically correlated) indices.

It is noted that the terms “vessel” and “lumen” are used interchangeablyin the present application. Both of the aforementioned terms should beconstrued to mean structures within the body that are shaped as lumens,for example, arteries and veins.

It is noted that the term “proximal” is used in the present applicationto denote a location within a lumen that is upstream of a givenreference location (such as a stenosis) within the lumen, and the term“distal” is used to denote a location within a lumen that is downstreamof a given reference location.

There is therefore provided, in accordance with some applications of thepresent invention, apparatus for use with an imaging device configuredto acquire a set of angiographic images of a lumen of a subject's body,and a display, the apparatus including:

at least one processor, including:

-   -   blood-velocity-determination functionality configured, via image        processing, to determine blood velocity within the lumen, by:        -   defining at least first and second regions of interest along            the lumen in one of the angiographic images;        -   identifying the regions of interest in at least some            additional angiographic images belonging to the set of            angiographic images;        -   determining a distance between the regions of interest;        -   determining that a presence of a contrast agent appears at            the first region of interest in a first one of the            angiographic images and that the presence of contrast agent            appears at the second region of interest in a second one of            the angiographic images; and        -   determining the time that it took for the contrast agent to            travel from the first region of interest to the second            region of interest, based upon an interval between an            acquisition of the first angiographic image and an            acquisition of the second angiographic image;    -   geometry-indication-receiving functionality configured to        receive an indication of geometry of the lumen at a given        location within the lumen;    -   current-flow-related-parameter-determination functionality        configured to determine a value of a current flow-related        parameter at the location based upon the determined blood        velocity and the geometry of the lumen in the vicinity of the        location;    -   flow-related-parameter-receiving functionality configured to        receive an indication of a value of a second flow-related        parameter of the subject;    -   index-determination functionality configured to determine a        value of a luminal-flow-related index of the subject at the        location, by determining a relationship between the value of the        current flow-related parameter and the value of the second        flow-related parameter; and    -   output-generation functionality configured to generate an output        on the display in response to the determined value of the        luminal-flow-related index.

For some applications, the given location includes a location in avicinity of a stenosis within the lumen, and the index-determinationfunctionality is configured to determine the value of theluminal-flow-related index of the subject at the location, bydetermining the value of the luminal-flow-related index in the vicinityof the stenosis.

For some applications, the index-determination functionality isconfigured to determine the value of the luminal-flow-related index ofthe subject at the location, by determining a value of functional flowreserve of the subject at the location.

For some applications, the index-determination functionality isconfigured to determine the value of the luminal-flow-related index ofthe subject at the location, by determining a value of instantaneouswave-free ratio of the subject at the location.

For some applications, the blood-velocity-determination functionality isconfigured to determine that the presence of the contrast agent appearsat the first region of interest in the first one of the angiographicimages and that the presence of contrast agent appears at the secondregion of interest in the second one of the angiographic images bydetermining that a given concentration of the contrast agent appears atthe first region of interest in the first one of the angiographic imagesand that the given concentration of contrast agent appears at the secondregion of interest in the second one of the angiographic images.

For some applications, the blood-velocity-determination functionality isconfigured to determine that the presence of the contrast agent appearsat the first region of interest in the first one of the angiographicimages and that the presence of contrast agent appears at the secondregion of interest in the second one of the angiographic images bydetermining that a bolus of the contrast agent appears at the firstregion of interest in the first one of the angiographic images and thatthe bolus of contrast agent appears at the second region of interest inthe second one of the angiographic images.

For some applications, the blood-velocity-determination functionality isconfigured to determine that the presence of the contrast agent appearsat the first region of interest in the first one of the angiographicimages and that the presence of contrast agent appears at the secondregion of interest in the second one of the angiographic images bydetermining that a given pattern of the contrast agent appears at thefirst region of interest in the first one of the angiographic images andthat the given pattern of contrast agent appears at the second region ofinterest in the second one of the angiographic images.

For some applications, the blood-velocity-determination functionality isconfigured to define at least first and second regions of interest alongthe lumen in one of the angiographic images by defining at least firstand second regions of interest along a center line of the lumen in oneof the angiographic images.

For some applications, the at least one processor further includesimage-stabilization functionality configured to generate a stabilizedimage stream of the lumen based upon the acquired angiographic images,and the output-generation functionality is configured to generate theoutput by driving the display to display the stabilized image stream,and by generating, at a location that corresponds to the location andthat is within the displayed image stream, an indication of the value ofthe flow-related index at the location.

For some applications, the output-generation functionality is configuredto generate the output by driving the display to display an indicationof the value of the flow-related index, using a color legend, on animage of the lumen.

For some applications, the current-flow-related-parameter-determinationfunctionality is configured to determine the value of the currentflow-related parameter at the location using a machine-learningclassifier, based upon at least the determined blood velocity and thegeometry of the lumen at the location.

For some applications, the index-determination functionality isconfigured to determine the relationship between the value of thecurrent flow-related parameter and the value of the second flow-relatedparameter by determining the relationship between the value of thecurrent flow-related parameter and the value of the second flow-relatedparameter using a machine-learning classifier.

For some applications, the output-generation functionality is configuredto generate the output by:

in response to the luminal-flow-related index passing a first thresholdvalue, generating an output indicating that treatment of the subject isrecommended; and

in response to the luminal-flow-related index passing a second thresholdvalue but not passing the first threshold value, generating an outputrecommending that the luminal-flow-related index be measured using asensor that is inserted into the lumen.

For some applications:

the location includes a location in the vicinity of a stenosis;

the flow-related-parameter-receiving functionality is configured toreceive the indication of the value of the second flow-related parameterof the subject by receiving an indication of a value of blood pressureof the subject at a location that is upstream of the stenosis;

the current-flow-related-parameter-determination functionality isconfigured to determine the value of the current flow-related parameterin the vicinity of the stenosis by determining a value of current bloodpressure in the vicinity of the stenosis based upon the determined bloodvelocity and the geometry of the lumen in the vicinity of the stenosis;and

the index-determination functionality is configured to determine therelationship between the value of the current flow-related parameter andthe value of the second flow-related parameter by comparing the currentblood pressure in the vicinity of the stenosis to the subject's bloodpressure at the location that is upstream of the stenosis.

For some applications, the flow-related-parameter-receivingfunctionality is configured to receive the indication of the value ofthe blood pressure of the subject at the location that is upstream ofthe stenosis by receiving an indication of a value of aortic bloodpressure of the subject.

For some applications, the flow-related-parameter-receivingfunctionality is configured to receive the indication of the value ofthe second flow-related parameter of the subject by receiving theindication of the value of the second flow-related parameter of thesubject, based upon patient history of the subject.

For some applications:

the flow-related-parameter-receiving functionality is configured toreceive the indication of the value of the second flow-related parameterof the subject by receiving at least one previously-acquiredangiographic image of the subject's lumen,

the flow-related-parameter-receiving functionality is further configuredto derive a value of flow within the lumen at a time of acquisition ofthe previously-acquired angiographic image,

the current-flow-related-parameter-determination functionality isconfigured to determine the value of the current flow-related parameterin the vicinity of the stenosis by determining a value of current flowat the location based upon the determined blood velocity and thegeometry of the lumen at the location; and

the index-determination functionality is configured to determine therelationship between the value of the current flow-related parameter andthe value of the second flow-related parameter by determining arelationship between the value of the current flow at the location andthe value of the derived flow within the lumen at the time ofacquisition of the previously-acquired angiographic image.

For some applications:

the flow-related-parameter-receiving functionality is configured toreceive the indication of the value of the second flow-related parameterof the subject by receiving at least one previously-acquiredangiographic image of the subject's lumen,

the flow-related-parameter-receiving functionality is further configuredto derive a value of blood velocity within the lumen at a time ofacquisition of the previously-acquired angiographic image,

the current-flow-related-parameter-determination functionality isconfigured to determine the value of the current flow-related parameterin the vicinity of the stenosis by determining a value of current bloodvelocity at the location based upon the determined blood velocity andthe geometry of the lumen at the location; and

the index-determination functionality is configured to determine therelationship between the value of the current flow-related parameter andthe value of the second flow-related parameter by determining arelationship between the value of the current blood velocity at thelocation and the value of the derived blood velocity within the lumen atthe time of acquisition of the previously-acquired angiographic image.

For some applications, the geometry-indication-receiving functionalityis configured to determine geometry of the lumen at the location, basedupon the received indication of the geometry of the lumen.

For some applications, the current-flow-related-parameter-determinationfunctionality is configured to determine the value of the currentflow-related parameter at the location using a machine-learningclassifier, based upon the determined lumen geometry and the determinedblood velocity.

For some applications, the geometry-indication-receiving functionalityis configured to:

receive the indication of the geometry of the lumen by receiving atleast one of the set of angiographic images, and

determine geometry of the lumen at the location by determining across-sectional area of the lumen by performing quantitative vesselanalysis on the at least one of the set of angiographic images.

For some applications, the geometry-indication-receiving functionalityis configured to:

receive the indication of the geometry of the lumen by receiving atleast one of the set of angiographic images, and

determine geometry of the lumen at the location by determining across-sectional area of the lumen by performing densitometry on the atleast one of the set of angiographic images.

For some applications, the flow-related-parameter-receivingfunctionality is configured to receive the indication of a value of asecond flow-related parameter of the subject by receiving anangiographic image of a second location within the lumen, and theflow-related-parameter-receiving functionality is configured todetermine geometry of the lumen at the second location within the lumen,by performing image processing on the angiographic image of the secondlocation within the lumen.

For some applications, the flow-related-parameter-receivingfunctionality is configured to determine geometry of the lumen at thesecond location within the lumen by determining a cross-sectional areaat the second location within the lumen by performing quantitativevessel analysis on the angiographic image of the second location withinthe lumen.

For some applications, the flow-related-parameter-receivingfunctionality is configured to determine geometry of the lumen at thesecond location within the lumen by determining a cross-sectional areaat the second location within the lumen by performing densitometry onthe angiographic image of the second location within the lumen.

For some applications, the flow-related-parameter-receivingfunctionality is configured to determine a value of flow at the secondlocation within the lumen based upon the determined geometry at thesecond location within the lumen and the determined blood velocity.

For some applications, the flow-related-parameter-receivingfunctionality is configured to determine the value of the flow at thesecond location within the lumen based upon the determined geometry atthe second location within the lumen and the determined blood velocity,using a machine-learning classifier.

There is further provided, in accordance with some applications of thepresent invention, a method for use with a set of angiographic images ofa lumen of a subject's body, the method including:

via image processing, determining blood velocity within the lumen, by:

-   -   defining at least first and second regions of interest along the        lumen in one of the angiographic images;    -   identifying the regions of interest in at least some additional        angiographic images belonging to the set of angiographic images;    -   determining a distance between the regions of interest;    -   determining that a presence of a contrast agent appears at the        first region of interest in a first one of the angiographic        images and that the presence of contrast agent appears at the        second region of interest in a second one of the angiographic        images; and    -   determining the time that it took for the contrast agent to        travel from the first region of interest to the second region of        interest, based upon an interval between an acquisition of the        first angiographic image and an acquisition of the second        angiographic image;

receiving an indication of geometry of the lumen at a given locationwithin the lumen;

determining a value of a current flow-related parameter at the locationbased upon the determined blood velocity and the geometry of the lumenin the vicinity of the location;

receiving an indication of a value of a second flow-related parameter ofthe subject;

determining a value of a luminal-flow-related index of the subject atthe location, by determining a relationship between the value of thecurrent flow-related parameter and the value of the second flow-relatedparameter; and

generating an output in response to the determined value of theluminal-flow-related index.

For some applications, the contrast agent is within the lumen due to aninjection of contrast agent into the lumen, and the method furtherincludes acquiring a plurality of endoluminal images of the lumen, theacquisition of the plurality of endoluminal images being facilitated bythe injection of the contrast agent.

There is further provided, in accordance with some applications of thepresent invention, apparatus for use with an imaging device configuredto acquire a set of angiographic images of a lumen of a subject's body,and a display, the apparatus including:

at least one processor including:

-   -   image-processing functionality configured to analyze temporal        changes in a density of a contrast agent at a given location        within the lumen;    -   lumen-characterization functionality configured, in response to        the analysis, to determine a characteristic of the lumen at the        location, the characteristic being selected from the group        consisting of: a presence of a stenosis in a vicinity of the        location, and a value of a luminal-flow-related index of the        subject at the location; and    -   output-generation functionality configured to generate an output        on the display in response to the determined characteristic of        the lumen.

For some applications, the lumen-characterization functionality isconfigured to determine the characteristic of the lumen at the location,using a machine learning classifier.

For some applications, the at least one processor further includesgeometry-indication-receiving functionality configured to determinegeometry of the lumen at the location, and the lumen-characterizationfunctionality is configured to determine the characteristic of the lumenat the location by determining the characteristic of the lumen at thelocation in response to the geometry of the vessel at the location andthe analysis of the temporal changes in the density of the contrastagent at the location.

For some applications, the lumen-characterization functionality isconfigured to determine the characteristic of the lumen at the locationby determining the value of the luminal-flow-related index of thesubject at the location.

For some applications, the lumen-characterization functionality isconfigured to determine the characteristic of the lumen at the locationby determining the presence of the stenosis in the vicinity of thelocation.

For some applications, the contrast agent includes contrast agent thatis administered to the subject's lumen according to a given protocol,and the lumen-characterization functionality is configured to determinethe characteristic of the lumen at the location by determining thecharacteristic of the lumen at the location based upon the temporalchanges in the density of the contrast agent at the given locationwithin the lumen and the given protocol.

For some applications, the lumen-characterization functionality isconfigured to determine the characteristic of the lumen at the location,using a machine learning classifier.

For some applications, the contrast agent includes contrast agent thatis administered to the subject's lumen according to a given time-densityprotocol, and the lumen-characterization functionality is configured todetermine the characteristic of the lumen at the location by comparingthe temporal changes in the density of the contrast agent at the givenlocation within the lumen to the time-density protocol according towhich the contrast agent was administered to the subject.

There is further provided, in accordance with some applications of thepresent invention, a method for use with a set of angiographic images ofa lumen of a subject's body, the method including:

via image processing, analyzing temporal changes in a density of acontrast agent at a given location within the lumen;

in response to the analysis, determining a characteristic of the lumenat the location, the characteristic being selected from the groupconsisting of: a presence of a stenosis in a vicinity of the location,and a value of a luminal-flow-related index of the subject at thelocation; and

in response thereto, generating an output.

For some applications, the contrast agent includes contrast agent thatis injected into the lumen, and the method further includes acquiring aplurality of endoluminal images of the lumen, the acquisition of theplurality of endoluminal images being facilitated by the injection ofthe contrast agent.

There is further provided, in accordance with some applications of thepresent invention, apparatus for use with an imaging device configuredto acquire a set of two-dimensional angiographic images of a lumen of asubject's body, and a display, the apparatus including:

at least one processor, including:

-   -   blood-velocity-determination functionality configured, without        generating a virtual three-dimensional model of the lumen, and        by performing image processing on the two-dimensional        angiographic images, to determine blood velocity within the        lumen;    -   geometry-indication-receiving functionality configured, without        generating a virtual three-dimensional model of the lumen, and        by performing image processing on the two-dimensional        angiographic images, to determine geometry of the lumen at a        given location within the lumen;    -   current-flow-related-parameter-determination functionality        configured to determine a value of a current flow-related        parameter at the location based upon the determined blood        velocity and the geometry of the lumen in the vicinity of the        location;    -   flow-related-parameter-receiving functionality configured to        receive an indication of a value of a second flow-related        parameter of the subject;    -   index-determination functionality configured to determine a        value of a luminal-flow-related index of the subject at the        location, by determining a relationship between the value of the        current flow-related parameter and the value of the second        flow-related parameter; and    -   output-generation functionality configured to generate an output        on the display in response to the determined value of the        luminal-flow-related index.

For some applications, the blood-velocity-determination functionality isconfigured to determine the blood velocity within the lumen by:

defining at least first and second regions of interest along the lumenin one of the angiographic images;

identifying the regions of interest in at least some additionalangiographic images belonging to the set of angiographic images;

determining a distance between the regions of interest;

determining that a presence of a contrast agent appears at the firstregion of interest in a first one of the angiographic images and thatthe presence of contrast agent appears at the second region of interestin a second one of the angiographic images; and

determining the time that it took for the contrast agent to travel fromthe first region of interest to the second region of interest, basedupon an interval between an acquisition of the first angiographic imageand an acquisition of the second angiographic image.

For some applications, the given location includes a location in avicinity of a stenosis within the lumen, and the index-determinationfunctionality is configured to determine the value of theluminal-flow-related index of the subject at the location, bydetermining the value of the luminal-flow-related index in the vicinityof the stenosis.

For some applications, the index-determination functionality isconfigured to determine the value of the luminal-flow-related index ofthe subject at the location, by determining a value of functional flowreserve of the subject at the location.

For some applications, the index-determination functionality isconfigured to determine the value of the luminal-flow-related index ofthe subject at the location, by determining a value of instantaneouswave-free ratio of the subject at the location.

For some applications, the at least one processor further includesimage-stabilization functionality configured to generate a stabilizedimage stream of the lumen based upon the acquired angiographic images,and the output-generation functionality is configured to generate theoutput by driving the display to display the stabilized image stream,and by generating, at a location that corresponds to the location andthat is within the displayed image stream, an indication of the value ofthe flow-related index at the location.

For some applications, the output-generation functionality is configuredto generate the output by driving the display to display an indicationof the value of the flow-related index, using a color legend, on animage of the lumen.

For some applications, the current-flow-related-parameter-determinationfunctionality is configured to determine the value of the currentflow-related parameter at the location based upon at least thedetermined blood velocity and the geometry of the lumen at the location,using a machine-learning classifier.

For some applications, the index-determination functionality isconfigured to determine the relationship between the value of thecurrent flow-related parameter and the value of the second flow-relatedparameter by determining the relationship between the value of thecurrent flow-related parameter and the value of the second flow-relatedparameter using a machine-learning classifier.

For some applications, the output-generation functionality is configuredto generate the output by:

in response to the luminal-flow-related index passing a first thresholdvalue, generating an output indicating that treatment of the subject isrecommended; and

in response to the luminal-flow-related index passing a second thresholdvalue but not passing the first threshold value, generating an outputrecommending that the luminal-flow-related index be measured using asensor that is inserted into the lumen.

For some applications, the geometry-indication-receiving functionalityis configured to determine the geometry of the lumen at the givenlocation within the lumen determining a cross-sectional area of thelumen by performing quantitative vessel analysis on at least one of theset of angiographic images.

For some applications, the geometry-indication-receiving functionalityis configured to determine the geometry of the lumen at the givenlocation within the lumen by performing densitometry on at least one ofthe set of angiographic images.

For some applications:

the location includes a location in the vicinity of a stenosis;

the flow-related-parameter-receiving functionality is configured toreceive the indication of the value of the second flow-related parameterof the subject by receiving an indication of a value of blood pressureof the subject at a location that is upstream of the stenosis;

the current-flow-related-parameter-determination functionality isconfigured to determine the value of the current flow-related parameterin the vicinity of the stenosis by determining a value of current bloodpressure in the vicinity of the stenosis based upon the determined bloodvelocity and the geometry of the lumen in the vicinity of the stenosis;and

the index-determination functionality is configured to determine therelationship between the value of the current flow-related parameter andthe value of the second flow-related parameter by comparing the currentblood pressure in the vicinity of the stenosis to the subject's bloodpressure at the location that is upstream of the stenosis.

For some applications, the flow-related-parameter-receivingfunctionality is configured to receive the indication of the value ofthe blood pressure of the subject at the location that is upstream ofthe stenosis by receiving an indication of a value of aortic bloodpressure of the subject.

For some applications, the flow-related-parameter-receivingfunctionality is configured to receive the indication of the value ofthe second flow-related parameter of the subject by receiving theindication of the value of the second flow-related parameter of thesubject, based upon patient history of the subject.

For some applications:

the flow-related-parameter-receiving functionality is configured toreceive the indication of the value of the second flow-related parameterof the subject by receiving at least one previously-acquiredangiographic image of the subject's lumen,

the flow-related-parameter-receiving functionality is further configuredto derive a value of flow within the lumen at a time of acquisition ofthe previously-acquired angiographic image,

the current-flow-related-parameter-determination functionality isconfigured to determine the value of the current flow-related parameterin the vicinity of the stenosis by determining a value of current flowat the location based upon the determined blood velocity and thegeometry of the lumen at the location; and

the index-determination functionality is configured to determine therelationship between the value of the current flow-related parameter andthe value of the second flow-related parameter by determining arelationship between the value of the current flow at the location andthe value of the derived flow within the lumen at the time ofacquisition of the previously-acquired angiographic image.

For some applications:

the flow-related-parameter-receiving functionality is configured toreceive the indication of the value of the second flow-related parameterof the subject by receiving at least one previously-acquiredangiographic image of the subject's lumen,

the flow-related-parameter-receiving functionality is further configuredto derive a value of blood velocity within the lumen at a time ofacquisition of the previously-acquired angiographic image,

the current-flow-related-parameter-determination functionality isconfigured to determine the value of the current flow-related parameterin the vicinity of the stenosis by determining a value of current bloodvelocity at the location based upon the determined blood velocity andthe geometry of the lumen at the location; and

the index-determination functionality is configured to determine therelationship between the value of the current flow-related parameter andthe value of the second flow-related parameter by determining arelationship between the value of the current blood velocity at thelocation and the value of the derived blood velocity within the lumen atthe time of acquisition of the previously-acquired angiographic image.

For some applications, the flow-related-parameter-receivingfunctionality is configured to receive the indication of a value of asecond flow-related parameter of the subject by receiving anangiographic image of a second location within the lumen, and theflow-related-parameter-receiving functionality is configured todetermine geometry of the lumen at the second location within the lumen,by performing image processing on the angiographic image of the secondlocation within the lumen.

For some applications, the flow-related-parameter-receivingfunctionality is configured to determine geometry of the lumen at thesecond location within the lumen by determining a cross-sectional areaat the second location within the lumen by performing quantitativevessel analysis on the angiographic image of the second location withinthe lumen.

For some applications, the flow-related-parameter-receivingfunctionality is configured to determine geometry of the lumen at thesecond location within the lumen by determining a cross-sectional areaat the second location within the lumen by performing densitometry onthe angiographic image of the second location within the lumen.

For some applications, the flow-related-parameter-receivingfunctionality is configured to determine a value of flow at the secondlocation within the lumen based upon the determined geometry at thesecond location within the lumen and the determined blood velocity.

For some applications, the flow-related-parameter-receivingfunctionality is configured to determine the value of the flow at thesecond location within the lumen based upon the determined geometry atthe second location within the lumen and the determined blood velocity,using a machine-learning classifier.

There is further provided, in accordance with some applications of thepresent invention, a method for use with a set of two-dimensionalangiographic images of a lumen of a subject's body, the methodincluding:

without generating a virtual three-dimensional model of the lumen, andby performing image processing on the two-dimensional angiographicimages:

-   -   determining blood velocity within the lumen; and    -   determining geometry of the lumen at a given location within the        lumen;

determining a value of a current flow-related parameter at the locationbased upon the determined blood velocity and the geometry of the lumenat the location;

receiving an indication of a value of a second flow-related parameter ofthe subject;

determining a value of a luminal-flow-related index of the subject atthe location, by determining a relationship between the value of thecurrent flow-related parameter and the value of the second flow-relatedparameter; and

generating an output in response to the determined value of theluminal-flow-related index.

There is further provided, in accordance with some applications of thepresent invention, apparatus for use with a lumen of a subject,including:

a pressure sensor configured to measure pressure of the lumen;

a blood velocity sensor configured to measure blood velocity within thelumen; and

at least one processor including:

-   -   lumen-dimension-derivation functionality configured to derive a        dimension of the lumen from the measured pressure and blood        velocity; and    -   output-generation functionality configured to generate an out        output in response to the derived dimension.

For some applications, the apparatus further includes a tool configuredto be inserted into the lumen, and the pressure sensor and the bloodvelocity sensor are both coupled to the tool.

For some applications, the lumen-dimension-derivation functionality isconfigured to derive the dimension of the lumen by deriving a length ofa portion of the lumen.

For some applications, the lumen-dimension-derivation functionality isconfigured to derive the dimension of the lumen by deriving across-sectional area of the lumen.

For some applications, the lumen-dimension-derivation functionality isconfigured to derive the dimension of the lumen by deriving a percentageocclusion of the lumen.

For some applications, the lumen-dimension-derivation functionality isconfigured to derive the dimension of the lumen by deriving a diameterof the lumen.

For some applications, the lumen-dimension-derivation functionality isconfigured to derive the diameter of the lumen by deriving a minimumlumen diameter of the lumen.

There is further provided, in accordance with some applications of thepresent invention, a method for use with a lumen of a subject,including:

measuring pressure of the lumen;

measuring blood velocity within the lumen;

deriving from the measured pressure and blood velocity, a dimension ofthe lumen; and

generating an output in response thereto.

For some applications, measuring pressure of the lumen includesmeasuring pressure of the lumen using a pressure sensor that is coupledto a medical device while the medical device is inside the lumen, andmeasuring blood velocity includes measuring blood velocity using a bloodvelocity sensor that is coupled to the medical device while the medicaldevice is inside the lumen.

There is further provided, in accordance with some applications of thepresent invention, apparatus for use with (a) an endoluminaldata-acquisition device configured to be moved through a lumen of asubject's body, and to acquire at least a first set of endoluminal datapoints of the lumen at a plurality of locations within the lumen, whilebeing moved through the lumen, (b) and extraluminal imaging deviceconfigured to acquire an extraluminal image of the lumen, and (c) adisplay, the apparatus including:

at least one processor, including:

-   -   endoluminal-geometry-derivation-functionality configured, for at        least some of the endoluminal data points, to derive from the        endoluminal data point a value of a geometrical parameter of the        lumen at a location within the lumen at which the endoluminal        data point was acquired;    -   extraluminal-geometry-derivation-functionality configured to        derive values of the geometrical parameter of the lumen at a        plurality of locations along the lumen, by performing image        processing on the at least one extraluminal image of the lumen;    -   co-registration functionality configured to co-register at least        some of the endoluminal data points to locations along the lumen        within the extraluminal image by correlating the values of the        geometrical parameters corresponding to the endoluminal data        points with the values of the geometrical parameter derived by        performing image processing on the at least one extraluminal        image; and    -   output-generation functionality configured to generate an output        on the display based upon the co-registration.

For some applications, the output-generation functionality is configuredto generate the output by generating an output indicating that a givenendoluminal data point corresponds to a given location along the lumen.

For some applications:

the endoluminal-geometry-derivation-functionality is configured toderive the value of the geometrical parameter of the lumen by deriving avalue of a geometrical parameter of the lumen selected from the groupconsisting of: a cross-sectional area of the lumen, and a diameter ofthe lumen; and

the extraluminal-geometry-derivation-functionality is configured toderive values of the geometrical parameter of the lumen, by derivingvalues of the selected geometrical parameter.

For some applications, the set of endoluminal data points includes a setof blood velocity data points that are indicative of blood velocitywithin the lumen at locations at which respective endoluminal datapoints belonging to the set of endoluminal data points were acquired,and the endoluminal-geometry-derivation-functionality is configured toderive from at least some of the blood velocity data points a value of ageometrical parameter of the lumen at a location within the lumen atwhich the blood velocity data point was acquired.

For some applications, the set of endoluminal data points includes a setof blood pressure data points that are indicative of blood pressurewithin the lumen at locations at which respective endoluminal datapoints belonging to the set of endoluminal data points were acquired,and the endoluminal-geometry-derivation-functionality is configured toderive from at least some of the blood pressure data points a value of ageometrical parameter of the lumen at a location within the lumen atwhich the blood pressure data point was acquired.

For some applications, the set of endoluminal data points includes a setof flow data points that are indicative of flow within the lumen atlocations at which respective endoluminal data points belonging to theset of endoluminal data points were acquired, and theendoluminal-geometry-derivation-functionality is configured to derivefrom at least some of the flow data points a value of a geometricalparameter of the lumen at a location within the lumen at which the flowdata point was acquired.

For some applications, the set of endoluminal data points includes a setof endoluminal images, and theendoluminal-geometry-derivation-functionality is configured to derivethe value of the geometrical parameter of the lumen at the locationwithin the lumen at which an endoluminal data point was acquired byderiving the value of the geometrical parameter of the lumen at thelocation within the lumen at which an endoluminal image was acquired byperforming image processing on the endoluminal image.

For some applications:

the endoluminal data-acquisition device includes an endoluminaldata-acquisition device that is further configured to acquire a secondset of endoluminal data points of the lumen at a plurality of locationswithin the lumen, while being moved through the lumen;

the co-registration functionality is configured, based upon theco-registering of the first set of endoluminal data points to locationsalong the lumen within the extraluminal image, to co-register the secondset of endoluminal data points to locations along the lumen within theextraluminal image; and

the output-generation functionality is configured to generate the outputby generating an output indicating that a given endoluminal data pointbelonging to the second set of endoluminal data points corresponds to agiven location along the lumen.

For some applications:

the first set of endoluminal data points includes a set of bloodvelocity data points that are indicative of blood velocity within thelumen at locations at which respective endoluminal data points belongingto the set of endoluminal data points were acquired;

the endoluminal-geometry-derivation-functionality is configured toderive from at least some of the blood velocity data points a value of ageometrical parameter of the lumen at a location within the lumen atwhich the blood velocity data point was acquired;

the second set of endoluminal data points includes a set of endoluminalimages; and

the output-generation functionality is configured to generate the outputby generating an output indicating that a given endoluminal imagecorresponds to a given location along the lumen.

For some applications:

the first set of endoluminal data points includes a set of bloodvelocity data points that are indicative of blood velocity within thelumen at locations at which respective endoluminal data points belongingto the set of endoluminal data points were acquired;

the endoluminal-geometry-derivation-functionality is configured toderive from at least some of the blood velocity data points a value of ageometrical parameter of the lumen at a location within the lumen atwhich the blood velocity data point was acquired;

the second set of endoluminal data points includes a set of endoluminalfunctional data points; and

the output-generation functionality is configured to generate the outputby generating an output indicating that a given endoluminal functionaldata point corresponds to a given location along the lumen.

For some applications, the co-registration functionality is configuredto co-register at least some of the endoluminal data points to locationsalong the lumen within the extraluminal image by correlating a sequenceof values of the geometrical parameters corresponding to the endoluminaldata points with a sequence of values of the geometrical parameterderived by performing image processing on the at least one extraluminalimage.

For some applications, the co-registration functionality is configuredto co-register at least some of the endoluminal data points to locationsalong the lumen within the extraluminal image by correlating a variationof the sequence of values of the geometrical parameters corresponding tothe endoluminal data points with a variation of the sequence of valuesof the geometrical parameter derived by performing image processing onthe at least one extraluminal image.

For some applications, the co-registration functionality is configuredto co-register at least some of the endoluminal data points to locationsalong the lumen within the extraluminal image by correlating amathematical derivative of the sequence of values of the geometricalparameters corresponding to the endoluminal data points with amathematical derivative of the sequence of values of the geometricalparameter derived by performing image processing on the at least oneextraluminal image.

There is further provided, in accordance with some applications of thepresent invention, a method for use with an endoluminal data-acquisitiondevice configured to be moved through a lumen of a subject's body, themethod including:

while the endoluminal data-acquisition device is being moved through thelumen, acquiring at least a first set of endoluminal data points of thelumen at a plurality of locations within the lumen, using theendoluminal data-acquisition device;

for at least some of the endoluminal data points, deriving from theendoluminal data point a value of a geometrical parameter of the lumenat a location within the lumen at which the endoluminal data point wasacquired;

acquiring at least one extraluminal image of the lumen;

deriving values of the geometrical parameter of the lumen at a pluralityof locations along the lumen, by performing image processing on the atleast one extraluminal image of the lumen;

co-registering at least some of the endoluminal data points to locationsalong the lumen within the extraluminal image by correlating the valuesof the geometrical parameters corresponding to the endoluminal datapoints with the values of the geometrical parameter derived byperforming image processing on the at least one extraluminal image; and

in response thereto, generating an output.

There is further provided, in accordance with some applications of thepresent invention, apparatus for use with (a) an endoluminaldata-acquisition device configured to be moved through a lumen of asubject's body, and to acquire at least a first set of endoluminal datapoints of the lumen at a plurality of locations within the lumen, whilebeing moved through the lumen, (b) an extraluminal imaging deviceconfigured to acquire at least one two-dimensional angiographic image ofthe lumen, and (c) a display, the apparatus including:

at least one processor including:

-   -   index-determination functionality configured to non-invasively        determine a value of a luminal-flow-related index of the subject        at a plurality of locations along the lumen, at least partially        by performing image processing on the two-dimensional        angiographic image;    -   co-registration functionality configured:        -   to determine that respective endoluminal data points            correspond to respective locations along the lumen, and        -   in response thereto, to determine that respective            endoluminal data points correspond to respective values of            the luminal flow-related index; and    -   output-generation functionality configured to generate an output        on the display based upon determining that respective        endoluminal data points correspond to respective values of the        luminal flow-related index.

For some applications, the index-determination functionality isconfigured to determine the value of the luminal-flow-related index ofthe subject at the plurality of locations along the lumen, bydetermining a value of functional flow reserve of the subject at theplurality of locations along the lumen.

For some applications, the index-determination functionality isconfigured to determine the value of the luminal-flow-related index ofthe subject at the plurality of locations along the lumen, bydetermining a value of instantaneous wave-free ratio of the subject atthe plurality of locations along the lumen.

For some applications, the output-generation functionality is configuredto generate the output by generating an output indicating that a givenendoluminal data point corresponds to a given value of the luminalflow-related index.

For some applications, the set of endoluminal data points includes a setof endoluminal images, and the output-generation functionality isconfigured to generate the output by generating an output indicatingthat a given endoluminal image corresponds to a given value of theluminal flow-related index.

For some applications, the set of endoluminal data points includes a setof endoluminal functional data points, and the output-generationfunctionality is configured to generate the output by generating anoutput indicating that a given endoluminal functional data pointcorresponds to a given value of the luminal flow-related index.

There is further provided, in accordance with some applications of thepresent invention, a method for use with an endoluminal data-acquisitiondevice configured to be moved through a lumen of a subject's body, andat least one two-dimensional angiographic image of the lumen, the methodincluding:

non-invasively determining a value of a luminal-flow-related index ofthe subject at a plurality of locations along the lumen, at leastpartially by performing image processing on the at least onetwo-dimensional angiographic image;

while the endoluminal data-acquisition device is being moved through thelumen, acquiring a set of endoluminal data points of the lumen at aplurality of locations within the lumen, using the endoluminaldata-acquisition device;

determining that respective endoluminal data points correspond torespective locations along the lumen;

in response thereto, determining that respective endoluminal data pointscorrespond to respective values of the luminal flow-related index; and

generating an output in response thereto.

There is further provided, in accordance with some applications of thepresent invention, apparatus for use with an imaging device configuredto acquire a plurality of angiographic image frames of a moving lumen ofa subject, and a display, the apparatus including:

at least one processor including:

-   -   blood-velocity-determination functionality configured to:        -   align the image frames with each other; and        -   using the aligned image frames, determine a time it takes a            contrast agent to travel a known distance through the lumen;    -   lumen-characterization functionality configured at least        partially in response to the determined time it takes the        contrast agent to travel the known distance through the lumen,        to determine a characteristic of the lumen; and    -   output-generation functionality configured, in response to the        determined characteristic, to generate an output on the display.

For some applications, the lumen-characterization functionality isconfigured to determine the characteristic of the lumen by determiningflow within the lumen.

For some applications, the lumen-characterization functionality isconfigured to determine the characteristic of the lumen by determining ahemodynamic characteristic of the lumen.

For some applications, the lumen-characterization functionality isconfigured to determine the characteristic of the lumen by:

determining geometry of the lumen, and

determining a value of a current flow-related parameter of the lumenbased upon the time it takes the contrast agent to travel the knowndistance through the lumen and the determined geometry of the lumen.

For some applications:

the at least one processor further includesflow-related-parameter-receiving functionality configured to receive anindication of a value of a second flow-related parameter of the subject;and

the lumen-characterization functionality is configured to determine thecharacteristic of the lumen by determining a value of aluminal-flow-related index of the subject at a given location within thelumen, by determining a relationship between the value of the currentflow-related parameter and the value of the second flow-relatedparameter.

For some applications, the given location includes a location in avicinity of a stenosis within the lumen, and the lumen-characterizationfunctionality is configured to determine the value of theluminal-flow-related index by determining the value of theluminal-flow-related index in the vicinity of the stenosis.

For some applications, the lumen-characterization functionality isconfigured to determine the value of the luminal-flow-related index bydetermining a value of functional flow reserve of the subject at thelocation.

For some applications, the lumen-characterization functionality isconfigured to determine the value of the luminal-flow-related index bydetermining a value of instantaneous wave-free ratio of the subject atthe location.

For some applications, the at least one processor is configured togenerate a stabilized image stream of the lumen based upon the acquiredangiographic images, and the output-generation functionality isconfigured to generate the output by driving the display to display thestabilized image stream, and by generating, at a location thatcorresponds to the location and that is within the displayed imagestream, an indication of the value of the flow-related index at thelocation.

For some applications, the output-generation functionality is configuredto generate the output by driving the display to display an indicationof the value of the flow-related index, using a color legend, on animage of the lumen.

For some applications, the lumen-characterization functionality isconfigured to determine the value of the luminal-flow-related indexbased upon the determined blood velocity and geometry of the lumen atthe location, using a machine-learning classifier.

For some applications, the lumen-characterization functionality isconfigured to determine the relationship between the value of thecurrent flow-related parameter and the value of the second flow-relatedparameter using a machine-learning classifier.

For some applications, the output-generation functionality is configuredto generate the output by:

in response to the luminal-flow-related index passing a first thresholdvalue, generating an output indicating that treatment of the subject isrecommended; and

in response to the luminal-flow-related index passing a second thresholdvalue but not passing the first threshold value, generating an outputrecommending that the luminal-flow-related index be measured using asensor that is inserted into the lumen.

There is further provided, in accordance with some applications of thepresent invention, a method for use with a plurality of angiographicimage frames of a moving lumen of a subject, the method including:

aligning the image frames with each other;

using the aligned image frames, determining a time it takes a contrastagent to travel a known distance through the lumen;

at least partially in response thereto, determining a characteristic ofthe lumen; and

in response to the determined characteristic, generating an output on adisplay.

For some applications, determining the characteristic of the lumenincludes determining flow within the lumen.

For some applications, determining the characteristic of the lumenincludes determining a hemodynamic characteristic of the lumen.

For some applications, determining the characteristic of the lumenincludes determining geometry of the lumen, and determining a value of acurrent flow-related parameter of the lumen based upon the time it takesthe contrast agent to travel the known distance through the lumen andthe determined geometry of the lumen.

For some applications, the method further includes:

receiving an indication of a value of a second flow-related parameter ofthe subject; and

determining a value of a luminal-flow-related index of the subject at agiven location within the lumen, by determining a relationship betweenthe value of the current flow-related parameter and the value of thesecond flow-related parameter.

For some applications, the given location includes a location in avicinity of a stenosis within the lumen, and determining the value ofthe luminal-flow-related index includes determining the value of theluminal-flow-related index in the vicinity of the stenosis.

For some applications, determining the value of the luminal-flow-relatedindex at the location includes determining a value of functional flowreserve of the subject at the location.

For some applications, determining the value of the luminal-flow-relatedindex of the subject at the location includes determining a value ofinstantaneous wave-free ratio of the subject at the location.

For some applications, the method further includes generating astabilized image stream of the lumen based upon the aligned angiographicimages, and generating the output includes generating an indication ofthe value of the flow-related index on the image stream.

For some applications, generating the output includes generating, on animage of the lumen, an indication of the value of the flow-relatedindex, using a color legend.

For some applications, determining the value of the current flow-relatedparameter at the location within the lumen includes, using amachine-learning classifier, determining the value of the currentflow-related parameter at the location within the lumen, based upon thedetermined blood velocity and geometry of the lumen at the location.

For some applications, determining the relationship between the value ofthe current flow-related parameter and the value of the secondflow-related parameter includes determining the relationship between thevalue of the current flow-related parameter and the value of the secondflow-related parameter using a machine-learning classifier.

For some applications, generating the output includes:

in response to the luminal-flow-related index passing a first thresholdvalue, generating an output indicating that treatment of the subject isrecommended; and

in response to the luminal-flow-related index passing a second thresholdvalue but not passing the first threshold value, generating an outputrecommending that the luminal-flow-related index be measured using asensor that is inserted into the lumen.

The present invention will be more fully understood from the followingdetailed description of embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of a processor that is used tocalculate a luminal-flow-related index, by means of image processing, inaccordance with some applications of the present invention;

FIG. 2 is a flow chart, at least some of the steps of which are used tocalculate a luminal-flow-related index, by means of image processing, inaccordance with some applications of the present invention;

FIG. 3A shows regions of an angiographic image at which the progress ofcontrast agent through the lumen is measured, in accordance with someapplications of the present invention;

FIG. 3B shows an illustrative example of time-density curves of acontrast agent measured at respective regions within a lumen, inaccordance with some applications of the present invention;

FIG. 4 shows an angiogram image with an FFR value calculated anddisplayed distally to a stenosis, in accordance with some applicationsof the present invention;

FIG. 5 is a schematic illustration of a processor that is used todetermine a characteristic of a lumen by means of image processing, inaccordance with some applications of the present invention;

FIG. 6 is a schematic illustration of a processor that is used tocalculate lumen dimensions and/or lumen geometry using blood velocityand pressure measurements, in accordance with some applications of thepresent invention; and

FIG. 7 is a schematic illustration of a processor that is used toco-register endoluminal data points to locations along the lumen withinan extraluminal image, in accordance with some applications of thepresent invention.

DETAILED DESCRIPTION OF EMBODIMENTS

-   -   The term “contrast agent,” when used in reference to its        application in conjunction with imaging, refers to any substance        that is used to highlight, and/or enhance in another manner, the        anatomical structure, functioning, and/or composition of a        bodily organ while the organ is being imaged.    -   The term “stabilized,” when used in the context of displayed        images, means a display of a series of images in a manner such        that periodic, cyclical, and/or other motion of the body        organ(s) being imaged, and/or of a medical tool being observed,        is partially or fully reduced, with respect to the entire image        frame, or at least a portion thereof    -   The term “automatic,” when used for describing the generation        and utilization of the road map, means “without necessitating        user intervention or interaction.” (Such interaction or        intervention may still however be optional in some cases.)    -   The term “real time” means without a noticeable delay.    -   The term “near real time” means with a short noticeable delay        (such as approximately one or two motion cycles of the        applicable organ, and, in the case of procedures relating to        organs or lumens the motion of which are primarily as a result        of the cardiac cycle, less than two seconds).    -   The term “on-line,” when used in reference to image processing,        or to measurements being made on images, means that the image        processing is performed, and/or the measurements are made,        intra-procedurally, for example, in real time or near real time.    -   The term “luminal-flow-related index” includes fractional flow        reserve (FFR), instantaneous wave-free ratio (iFR), coronary        flow reserve (CFR), index of microcirculatory resistance (IMR),        microvascular resistance index (MVRI), TIMI myocardial perfusion        grade (TMPG), relative fractional flow reserve (RFFR), and/or        other related indices (e.g., indices that are statistically        correlated with one or more of the aforementioned indices).

Reference is now made to FIG. 1, which is a schematic illustration of aprocessor 10 that is used to calculate a luminal-flow-related index, bymeans of image processing, in accordance with some applications of thepresent invention. Typically the processor calculates theluminal-flow-related index at a location within a lumen (e.g., alocation in the vicinity of a stenosis) of the subject based upon imageprocessing of angiographic images of the lumen that are acquired by animaging device 12. Processor 10 is typically used to perform theprocedure described with respect to FIG. 2. Processor 10 typicallyreceives inputs via the imaging device and via a user interface 13, andgenerates an output on display 24. For some applications, the userinterface includes a keyboard, a mouse, a trackball, a joystick, atouchscreen monitor, a touchpad, a voice-command interface, and/or othertypes of user interfaces that are known in the art. Typically, thedisplay includes a monitor. For some applications, the display includesa head-up display and/or a head-mounted display, such as Google Glass.Processor 10 typically includes at least some of the followingfunctionalities, the functions of which are described in further detailhereinbelow: geometry-indication-receiving functionality 14,blood-velocity-determination functionality 16, image-stabilizationfunctionality 17, current-flow-related-parameter-determinationfunctionality 18, flow-related-parameter-receiving functionality 19,lumen-characterization functionality 20, index-determinationfunctionality 21, and/or output-generation functionality 22. For someapplications, more than one processor is used to perform theaforementioned functionalities. For some applications, the at least oneprocessor performs only a portion of the aforementioned functionalities.

For some applications, processor 10 includesgeometry-indication-receiving functionality 14 that receives anindication of the geometry of the lumen. Typically, thegeometry-indication-receiving functionality receives at least one of theangiographic images, and automatically determines geometry of the lumenat a location within the lumen (e.g., in a vicinity of a stenosis withinthe lumen), by performing image processing on at least one of theangiographic images. For some applications, the aforementioned geometricmeasurements include quantitative vessel analysis, e.g., quantitativecoronary analysis (QCA). For some applications, QCA is performed in anautomated manner, typically on line, using techniques described in WO10/058398 to Cohen, US 2010/0172556 to Cohen, and/or US 2010/0228076 toBlank, all of which applications are incorporated herein by reference.It is noted that, typically, geometry-indication-receiving functionalitydetermines geometry of the lumen solely by performing image processingon two-dimensional angiographic images. Further typically,geometry-indication-receiving functionality determines geometry of thelumen without generating a three-dimensional model of the lumen.

For some applications, and typically in order to account for potentialasymmetry in the geometry of the lumen around its longitudinal axis,angiographic images of the lumen are acquired from two or more differentviewing angles, and the lumen geometry is determined based upon the twoor more angiographic images (e.g., by performing QCA on the two or moreangiographic images). Typically, in the case of angiographic images ofthe lumen being acquired from two or more different viewing angles, theviewing angles (or at least two of the viewing angles) form an anglewith one another of at least thirty degrees. The resulting two or moremeasured diameters, or two or more sets of measured diameters, are usedto calculate the cross-sectional area of the lumen (e.g., thecross-sectional area in the vicinity of the stenosis, and/or at otherlocations along the lumen (e.g., within a healthy portion of thelumen)). For some applications, and typically in order to facilitatemeasurements, a two-dimensional model is generated for one or morecross-sections of the lumen, and the lumen geometry is determined basedupon the two-dimensional model. For some applications and typically inorder to facilitate measurements, a three-dimensional model of a lumensection is generated, and the lumen geometry is determined based uponthe three-dimensional model. For some applications, typically for thepurpose of generating the two-dimensional or the three-dimensionalmodel, the lumen is assumed to be symmetrical around its longitudinalaxis. For some applications, typically in order to account for potentialforeshortening of the lumen as viewed from a single specific angle, QCAis performed on angiographic images acquired from two or more differentviewing angles, and the resulting two or more measured lengths, or twoor more sets of length measurements, are used to calculate the length ofthe lumen.

For some applications, geometry-indication-receiving functionality 14determines the cross-sectional area of the lumen in the vicinity of thestenosis, and/or at other locations along the lumen (e.g., within ahealthy portion of the lumen) by performing densitometry on at least oneof the angiographic images, in accordance with the techniques describedhereinbelow.

Processor 10 typically includes blood-velocity-determinationfunctionality 16 that automatically determines blood velocity within thelumen, by performing image processing on the angiographic imagesequence. It is noted that, typically, blood-velocity-determinationfunctionality 16 automatically determines blood velocity within thelumen solely by performing image processing on two-dimensionalangiographic images. Further typically, blood-velocity-determinationfunctionality 16 automatically determines blood velocity within thelumen without generating a three-dimensional model of the lumen.

For some applications, image-stabilization functionality 17 of processor10 is configured to generate a stabilized image stream of the lumen. Forsome applications of the present invention, on-line geometric and/orhemodynamic measurements (e.g., size, flow, ejection fraction) aredetermined by the processor, for example, by utilizing the stabilizedimage stream, in accordance with techniques described in US 2008/0221442to Tolkowsky, which is incorporated herein by reference. For someapplications, the stabilized image stream is used for on-linemeasurement of the flow within a lumen, by measuring the time it takescontrast agent to travel a known distance, e.g., in accordance withtechniques described in US 2008/0221442 to Tolkowsky, which isincorporated herein by reference.

For some applications, the aforementioned hemodynamic measurementsinclude measuring the time it takes contrast agent to travel a knowndistance, i.e., measuring the velocity of the contrast agent, andthereby measuring the velocity of blood flow through the lumen (e.g., asdescribed in further detail with reference to FIG. 2). For someapplications, such measurements include, typically automatically, bymeans of image processing, measuring the movement and/or theconcentration of contrast agent within the lumen. For some applications,such measurements include, typically automatically, by means of imageprocessing, measuring the location and/or darkness of pixelscorresponding to contrast agent within the lumen, which typically servesas a further indication of the quantity and/or the concentration of thecontrast agent in the blood flow. For some applications, suchmeasurements are performed, typically automatically, by means of imageprocessing, proximally and/or distally to the stenosis.

For some applications, parameters associated with the injection of thecontrast agent for the angiograms are known, which typically facilitatesthe aforementioned calculations. For example, the duration, quantity,concentration, pressure and/or flow of the contrast agent may be known.For some applications, the contrast agent is injected at a known patternof known quantities and concentrations along a known time line, whichtypically facilitates the aforementioned calculations.

For some applications, the contrast agent is injected for the angiogramswith an automated injection device such as the ACIST CVi® injectionsystem manufactured by ACIST Medical Systems (Minnesota, USA).Typically, the use of such an automated device facilitates determinationand control of some or all of the aforementioned parameters.

For some applications, the automated injection device is programmed toinject contrast agent such that the contrast agent replaces all theblood in the coronary blood vessels for a period of time. For someapplications, this facilitates measurement of blood flow by measuringthe time the contrast agent is evacuated from a section of known volumeof the blood vessel.

For some applications, the automated injection device is programmed toinject pulses of contrast agent in a predetermined pattern. For someapplications, a series of pulses is used to measure blood velocity in amore precise manner by using time-density curves. For some applications,a series of pulses is used to measure blood velocity throughout thecardiac cycle by using time-density curves.

For some applications, the aforementioned hemodynamic measurements aremade upon the aforementioned stabilized image stream. For someapplications, the stabilized image stream is generated using techniquesdescribed in US 2008/0221442 to Tolkowsky, which is incorporated hereinby reference. For some applications, the stabilized image stream isgenerated using techniques described in WO 10/058398 to Cohen, US2010/0172556 to Cohen, and/or US 2010/0228076 to Blank, all of whichapplications are incorporated herein by reference. Typically,stabilization is performed by aligning images with one another withrespect to a luminal section that contains the stenosis, or with respectto a location within the stenosis (such as the location of the minimallesion diameter of the stenosis). Typically, automatic measurement ofthe progress of the contrast agent along the lumen is facilitated byaligning the angiographic images with each other, and/or by generating astabilized image stream. For example, blood-velocitydetermination-functionality 16 may automatically align two of theangiographic images with one another, the times at which the respectiveimages were acquired being separated by a given time period. Theblood-velocity-determination functionality may then identify thelocation of a portion of the contrast agent in each of the two images(e.g., by identifying a pixel corresponding to the portion of thecontrast agent that is furthest downstream), and may thereby determine adistance travelled by the contrast agent during the time period thatseparated the acquisition of the two images.

For some applications, the stabilized image stream is also enhanced. Forsome applications, such enhancement is performed using techniquesdescribed in WO 10/058398 to Cohen, US 2010/0172556 to Cohen, and/or US2010/0228076 to Blank, all of which applications are incorporated hereinby reference.

For some applications, the stabilized image stream is displayed ondisplay 24. Hemodynamic measurements (such as the velocity of bloodthrough the lumen) are performed (e.g., in accordance with thetechniques described hereinabove), and the flow measurements aredisplayed upon the stabilized image stream. For some applications, flowmeasurements are displayed upon an image stream that has been bothstabilized and enhanced.

In general, the scope of the present invention includes performing thefollowing technique on a plurality of angiographic image frames of amoving lumen of a body, based upon techniques described in US2008/0221442 to Tolkowsky, which is incorporated herein by reference:

1) aligning the image frames with each other, to reduce imaged motion ofthe portion of the subject's body, e.g., using image-stabilizationfunctionality 17;

2) using the aligned image frames, determining a time it takes contrastagent to travel a known distance through the lumen, e.g., usingblood-velocity-determination functionality 16;

3) at least partially in response thereto, determining a characteristicof the lumen, e.g., using lumen-characterization functionality 20; and

4) in response to the determined characteristic, generating an output ona display, e.g., using output-generation functionality 22.

For some applications, flow and/or another hemodynamic characteristic ofthe lumen is determined. For some applications, geometry of the lumen isdetermined, and the value of a current flow-related parameter of thelumen in the vicinity of a stenosis is determined based upon the time ittakes the contrast agent to travel the known distance through the lumenand the determined geometry of the lumen. For some applications, anindication of the value of a second flow-related parameter of thesubject is received, e.g., using flow-related-parameter receivingfunctionality 19, and the value of a luminal-flow-related index of thesubject in the vicinity of the stenosis is determined, by determining arelationship between the current flow-related parameter and the secondflow-related parameter. For some applications, techniques describedherein for determining a luminal-flow-related index are combined withtechniques described in US 2008/0221442 to Tolkowsky, which isincorporated herein by reference.

Typically, processor 10 includescurrent-flow-related-parameter-determination functionality 18. Thecurrent-flow-related-parameter-determination functionality uses theaforementioned geometrical measurements in conjunction with theaforementioned hemodynamic measurements in order to compute the value ofa current flow-related parameter (e.g., blood pressure, blood velocity,or flow) at a given location in the lumen (e.g., in the vicinity of astenosis), as will be further detailed in subsequent sections of thedescription of embodiments of the current invention.

Further typically, processor 10 includesflow-related-parameter-receiving functionality 19. In order to calculatethe subject's luminal-flow-related index, the processor receives anindication of the value of a flow-related parameter (such as pressure,flow, or blood velocity) at a second location within a lumen of thesubject, or an indication of the value of a flow-related parameter (suchas pressure, flow, or blood velocity) at the given location within thelumen (e.g., in the vicinity of the stenosis) at a time when the lumenwas healthy. For example, the processor may receive an indication of thesubject's aortic pressure and may calculate the subject's luminalflow-related index by assuming that the pressure immediately upstream ofthe stenosis is equal to the subject's aortic pressure. For someapplications, aortic pressure is measured via a pressure sensor that iscoupled to a guiding catheter, and aortic pressure receivingfunctionality receives an indication of the subject's aortic pressurefrom the pressure sensor. For some applications, the aortic pressureserves as an input for the calculation of the pressure proximal to thestenosis, typically, by the pressure proximal to the stenosis beingassumed to be equal to the aortic pressure. Alternatively oradditionally, the value of a flow-related parameter (such as pressure,flow, or blood velocity) at the second location within the lumen may bedetermined by performing image-processing on an angiographic image ofthe second location. For example, the geometry of the lumen at thesecond location may be determined using the techniques described herein,and blood pressure, blood velocity and/or flow at the second locationmay thereby be determined, using the techniques described herein.

For some applications, the processor receives an indication of the valueof a flow-related parameter within the subject's lumen at a time whenthe subject was healthy, by receiving data relating to the subject'spatient history. For example, the processor may receive at least oneangiographic image of the subject's lumen that was acquired at a timewhen the subject was healthy, as described hereinbelow. The processormay derive flow or blood velocity within the lumen at the time of theacquisition of the previously-acquired image (i.e., at the time when thelumen was healthy), by performing image processing on thepreviously-acquired image.

Typically, processor 10 includes index-determination functionality 21,which is configured to determine the subject's luminal-flow-relatedindex (e.g., FFR) based upon input from at least some of the otherfunctionalities of the processor. As described hereinabove, theaforementioned geometrical measurements are used in conjunction with theaforementioned hemodynamic measurements to compute a currentflow-related parameter (e.g., blood pressure, blood velocity, or flow)in the vicinity of the stenosis, as will be further detailed insubsequent sections of the description of embodiments of the currentinvention. The subject's luminal flow-related parameter is determined bycomparing the value of the current flow-related parameter to the valueof the flow-related parameter the indication of which was received byflow-related-parameter-receiving functionality 19, as describedhereinabove. For some applications, such computations are madeautomatically. For some applications, such computations are made online.

For some applications, the pressure drop induced by a stenosis iscalculated and is then used to calculate a luminal-flow-related index(e.g., FFR). For example, the pressure drop induced by the stenosis maybe determined by (a) determining the current pressure in the vicinity ofthe stenosis based upon the geometrical measurements and the hemodynamicmeasurements that are determined by the processor, and (b) comparing thecurrent pressure in the vicinity of the stenosis to blood pressure at alocation upstream of the stenosis (e.g., the subject's aortic pressure).For some applications, a luminal-flow-related index (e.g., FFR) isdetermined by (a) determining the current flow or blood velocity in thevicinity of the stenosis based upon the geometrical measurements and thehemodynamic measurements that are determined by the processor, and (b)comparing the current flow or blood velocity in the vicinity of thestenosis to historical flow or blood velocity within the lumen, at atime when the lumen was healthy.

Typically, in response to the FFR or another index being determined,output-generation functionality 22 of the processor drives display 24 todisplay an output, e.g., as described hereinbelow with reference to FIG.4.

Reference is now made to FIG. 2, which is a flow chart, at least some ofthe steps of which are used to calculate a luminal-flow-related index,by means of image processing, in accordance with some applications ofthe present invention. It is noted that, for some applications, some ofthe steps shown in FIG. 2 may be practiced, without all of the stepsshown in FIG. 2 necessarily being practiced in combination. Typically,at least the steps that are marked with asterisks in FIG. 2 areperformed automatically.

In step 1, one or more angiographic image streams are acquired. For someapplications, processor 10 automatically determines that an angiogramhas commenced and/or has ended, for example, in accordance withtechniques described in WO 10/058398 to Cohen, US 2010/0172556 to Cohen,and/or US 2010/0228076 to Blank, all of which applications areincorporated herein by reference. For some applications, thedetermination that an angiogram has commenced and/or has ended isperformed in real time or near real time, for example, in accordancewith techniques described in WO 10/058398 to Cohen, US 2010/0172556 toCohen, and/or US 2010/0228076 to Blank, all of which applications areincorporated herein by reference.

In step 2, at least one suitable angiographic frame is selected from theangiographic sequence by processor 10. For some applications, theselection of the frame is performed automatically, and/or in real timeor near real time, for example, in accordance with techniques describedin WO 10/058398 to Cohen, US 2010/0172556 to Cohen, and/or US2010/0228076 to Blank, all of which applications are incorporated hereinby reference.

In step 3, the user indicates the location of interest, which istypically the area of a stenosis in the lumen. For some applications,processor 10 identifies the location of a stenosis at least partiallyautomatically, for example, in accordance with techniques described inWO 10/058398 to Cohen, US 2010/0172556 to Cohen, and/or US 2010/0228076to Blank, all of which applications are incorporated herein byreference. For example, a user may designate a single location in animage that is at or near a given location of a given blood vessel in theimage (e.g., using user interface 13, the user may click at or near thegiven location). For some applications, in response to the userdesignating the single location, the system automatically detects astenosis in the vicinity. For example, the system may identify edgelines and the reference diameters of the stenosis.

In step 4, quantitative measurements of the lumen geometry (e.g., QCAmeasurements) are performed by geometry-indication-receivingfunctionality 14. For some applications, QCA measurements are performedautomatically and/or in real time or near real time, for example, inaccordance with techniques described in WO 10/058398 to Cohen, US2010/0172556 to Cohen, and/or US 2010/0228076 to Blank, all of whichapplications are incorporated herein by reference. For someapplications, in step 4 of the procedure, the cross-sectional area ofthe lumen in the vicinity of the stenosis, and/or at other locationsalong the lumen (e.g., within a healthy portion of the lumen), isdetermined by performing densitometry on at least one of theangiographic images, in accordance with the techniques describedhereinbelow.

In step 5, additional image frames in the angiographic image stream arealigned with one another, for example, by aligning the image frames witheach other with respect to the location of the stenosis within the imageframes. For some applications, alignment is performed automaticallyand/or in real time or near real time, for example, in accordance withtechniques described in US 2008/0221442 to Tolkowsky, WO 10/058398 toCohen, US 2010/0172556 to Cohen, and/or US 2010/0228076 to Blank, all ofwhich applications are incorporated herein by reference. Typically, thealignment is performed such as to generate a stabilized angiographicimage stream, for example, in accordance with techniques described in US2008/0221442 to Tolkowsky, WO 10/058398 to Cohen, US 2010/0172556 toCohen, and/or US 2010/0228076 to Blank, all of which applications areincorporated herein by reference. For some applications, the alignmentis performed such as to generate an angiographic image stream that isboth stabilized and enhanced, for example, in accordance with techniquesdescribed in WO 10/058398 to Cohen, US 2010/0172556 to Cohen, and/or US2010/0228076 to Blank, all of which applications are incorporated hereinby reference.

For some applications, the QCA performed in step 4 on the suitable frameselected in step 2 is preceded by enhancement of the suitable frameselected in frame 2. Such enhancement is typically performed accordingto the techniques described with reference to step 5, e.g., inaccordance with techniques described in WO 10/058398 to Cohen, US2010/0172556 to Cohen, and/or US 2010/0228076 to Blank, all of whichapplications are incorporated herein by reference.

In steps 6 and 7, which may be performed in combination with oneanother, the progress and density of the contrast agent along theluminal section proximal and/or distal to the stenosis, and/or otherhemodynamic parameters, are measured by blood-velocity-determinationfunctionality 16. For some applications, such measurements are performedautomatically, for example, in accordance with techniques describedhereinabove with reference to FIG. 1. For some applications, suchmeasurements are performed in real time or near real time. For someapplications, such measurements are performed for one or more regionslocated along the luminal section. For some applications, such regionsare selected automatically. Typically, such regions are located alongthe center line of the luminal section. For some applications, thecenter line is determined automatically, for example, in accordance withtechniques described in WO 10/058398 to Cohen, US 2010/0172556 to Cohen,and/or US 2010/0228076 to Blank, all of which applications areincorporated herein by reference.

Reference is made to FIG. 3A, which shows regions of an angiographicimage at which the progress of contrast agent through the lumen ismeasured, in accordance with some applications of the present invention.FIG. 3A is a sample frame taken from an angiographic image stream.Regions 31 and 32 comprise a pair of regions along the center line ofthe lumen. Reference is also made to FIG. 3B, which shows anillustrative example of time-density curves of a contrast agent measuredat region 31 (the solid curve) and region 32 (the dashed curve). Forsome applications, blood-velocity-determination functionality 16determines the blood velocity at a region within the lumen by comparingthe contrast agent time-density curves at proximal and distal locationswithin the region. The blood-velocity-determination functionality 16thereby determines the time taken for the contrast agent to flow fromthe proximal location to the distal location. For example,blood-velocity-determination functionality 16 may determine that a givenpeak of the time-density curve appears at region 31 in a firstangiographic image, and that the peak appears at region 32 in a secondangiographic image. The blood-velocity-determination functionality maythereby determine the time that it took for the contrast agent to travelfrom the first region of interest to the second region of interest,based upon an interval (e.g., a time interval and/or a number of imageframes) between an acquisition of the first angiographic image and anacquisition of the second angiographic image.

Typically, the blood-velocity-determination functionality is configuredto determine blood velocity within the lumen by (a) defining at leastfirst and second regions of interest along the lumen in one of theangiographic images, (b) identifying the regions of interest in at leastsome additional angiographic images belonging to the set of angiographicimages, (c) determining a distance between the regions of interest, and(d) determining that a presence of a contrast agent (e.g., a bolus ofcontrast agent, a given concentration of contrast agent, and/or a givenpattern of contrast agent) appears at the first region of interest in afirst one of the angiographic images and that the presence of contrastagent appears at the second region of interest in a second one of theangiographic images.

Reference is again made to FIG. 2. In step 8, the aforementioned lumengeometry and hemodynamic measurements are utilized to calculate acurrent flow-related parameter of the lumen in the vicinity of thestenosis, typically, by means ofcurrent-flow-related-parameter-determination functionality 18.

In step 9, the luminal-flow-related index is calculated in the vicinityof the stenosis (e.g., along the luminal section comprising thestenosis), typically by means of index-determination functionality 21.For some applications, the index is calculated with respect to aspecific stenosis which was indicated by the user, and/or identified bythe processor, in step 3. For some applications, the index is calculatedfor multiple locations along a luminal section.

As described hereinabove, for some applications, the pressure dropinduced by the stenosis is determined and is then used to calculate aluminal-flow-related index (e.g., FFR). For example, the pressure dropinduced by the stenosis may be determined by (a) determining the currentpressure in the vicinity of the stenosis, based upon the geometricalmeasurements and the hemodynamic measurements that are determined by theprocessor, and (b) comparing the current pressure in the vicinity of thestenosis to blood pressure at a location upstream of the stenosis (e.g.,the subject's aortic pressure). For some applications, aluminal-flow-related index (e.g., FFR) is calculated by (a) determiningthe current flow or blood velocity in the vicinity of the stenosis,based upon the geometrical measurements and the hemodynamic measurementsthat are determined by the processor, and (b) comparing the current flowor blood velocity in the vicinity of the stenosis to historical flow orblood velocity within the lumen at a time when the lumen was healthy.Alternatively or additionally, a flow-related parameter (such aspressure, flow, or blood velocity) at a second location within the lumenis determined by performing image-processing on an angiographic image ofthe second location. For example, the geometry of the lumen at thesecond location may be determined using the techniques described herein,and blood pressure, blood velocity and/or flow at the second locationmay thereby be determined, using the techniques described herein. Aluminal flow-related index is determined by comparing the value of theflow-related parameter at the location of interest to the value of theflow-related parameter at the second location.

In step 10, output-generation functionality 22 drives display 24 todisplay the luminal-flow-related index. For some applications, a singlevalue corresponding to the specific stenosis is displayed. For someapplications, multiple values are displayed along the luminal sectioncomprising the stenosis. For some applications, the index is displayedupon an angiogram frame, such as the frame selected in step 2. For someapplications, the parameter is displayed upon an image stream that isstabilized with respect to the stenosis, e.g., a stabilized image streamas described hereinabove.

Reference is made to FIG. 4, which shows an angiogram image 41 with anFFR value 42 calculated and displayed distally to a stenosis, inaccordance with some applications of the present invention. For someapplications of the present invention, an FFR value (or the value ofanother luminal flow-related index) at a given site along a lumen isdisplayed on an image of the lumen (e.g., on a selected raw angiographicimage, on a stabilized angiographic image stream, on an enhancedangiographic image frame, and/or on a stabilized and enhancedangiographic image stream) at a location within the image (or imagestream) corresponding to the site. For example, in image 41, an FFRvalue of 0.7 corresponds to a lumen location 43 that is downstream ofstenotic section 44 in lumen 45. For some applications, the lumen isdisplayed in a manner that indicates the FFR values of respectivelocations along the lumen. For example, a legend 46, according to whichdifferent FFR values are assigned respective colors and/or patterns maybe used, and the lumen may be displayed in a manner that indicates theFFR values of respective locations along the lumen, in accordance withthe legend. For example, lumen 45, in the area of stenotic section 44,is colored with respect to calculated FFR values according to FFR colorlegend 46. (It is noted that, since FIG. 4 is shown in black-and-white,the legend appears in black-and-white. However, a color legend istypically used to indicate FFR values of locations along the lumen.) Forsome applications, QCA parameters 47 for the stenotic section 44 aredisplayed on the angiographic image and/or the angiographic imagestream. For some applications, an enhanced image of stenotic section 44is displayed in window 48, and/or a stabilized clip of lumen 45 isdisplayed in window 49. For some applications, the aforementioned FFRcalculations, QCA, enhancement and/or stabilization are all performed byprocessor 10, typically on line, in response to the user's indication(e.g., via user interface 13) of the location of the stenosis, or inresponse to the system automatically identifying the stenosis, e.g., inresponse to an input from the user.

For some applications, in response to determining that the subject's FFRpasses a first threshold value, an output is generated on the displayindicating that treatment of the subject (e.g., by deploying a stent atthe stenosis) is recommended. For example, by way of illustration, inresponse to determining that the FFR of the stenosis is less than 0.75,an output may be generated indicating that treatment of the subject isrecommended. For some applications, in response to determining that thesubject's FFR passed a second threshold value but did not pass the firstthreshold value, an output is generated on the display recommending thatthe luminal-flow-related index be determined using a sensor that isinserted into the lumen (e.g., by inserting a wire equipped withpressure sensors into the lumen). For example, by way of illustration,in response to determining that the FFR of the stenosis is less than 0.8but not less than 0.75 (i.e., in response to determining that thesubject's FFR is between 0.8 and 0.75), an output may be generatedrecommending that the luminal-flow-related index be determined using asensor that is inserted into the lumen.

For some applications, Instantaneous wave-Free Ratio (iFR), or aparameter that is related to iFR (e.g., by being statisticallycorrelated with iFR) is determined by processor 10, as an alternativeto, or in addition to the processor determining FFR. Typically, theprocessor determines iFR using generally similar techniques to thosedescribed herein for determining FFR. iFR is a pressure-derived index ofstenosis severity the determination of which, unlike typical FFR, doesnot typically require pharmacologic vasodilation. iFR has been describedas providing a drug-free index of stenosis severity comparable to FFR(Sian Sen et al., “Development and Validation of a New,Adenosine-Independent Index of Stenosis Severity From CoronaryWave-Intensity Analysis,” Journal of the American College of Cardiology,Vol. 59 2012).

For some applications, another luminal-flow-related index, for example,one of the luminal-flow-related indices described hereinabove, isdetermined by processor 10, as an alternative to, or in addition to theprocessor determining FFR. Typically, the processor determines the otherindex using generally similar techniques to those described herein fordetermining FFR, mutatis mutandis. Further typically, the other index isdisplayed in a generally similar manner to that described with referenceto FFR, mutatis mutandis.

For some applications, a luminal-flow-related index of a subject isdetermined based upon an angiographic image stream of the subject'slumen, via a procedure that includes at least some of the followingsteps:

-   -   1. A healthcare professional induces a hyperemic condition        within the subject's lumen. It is noted that this step is        optional, since the determination of some luminal-flow related        indices is not dependent on inducing a hyperemic condition        within the subject's lumen.    -   2. A healthcare professional initiates a cine angiogram of the        lumen.    -   3. In response to the healthcare professional initiating the        angiogram, processor 10 simultaneously acquires an x-ray image        stream of the lumen (e.g., a high-resolution x-ray image stream        of the lumen) and the subject's ECG signal.    -   4. Angiogram-detecting functionality (not shown) of processor 10        automatically determines that an angiogram has commenced and/or        has ended, for example, in accordance with techniques described        in WO 10/058398 to Cohen, US 2010/0172556 to Cohen, and/or US        2010/0228076 to Blank, all of which applications are        incorporated herein by reference. For some applications, the        identification that an angiogram has commenced and/or has ended        is performed in real time or near real time, for example, in        accordance with techniques described in WO 10/058398 to Cohen,        US 2010/0172556 to Cohen, and/or US 2010/0228076 to Blank, all        of which applications are incorporated herein by reference.    -   5. Processor 10 analyzes the subject's ECG signal.    -   6. Processor 10 selects a suitable angiographic image frame(s)        for analysis, typically in response to the analysis of the ECG        signal. For example, the processor may select the image with the        highest contrast that is near a QRS complex. For some        applications, steps 5 and 6 are performed in accordance with        techniques described in WO 10/058398 to Cohen, US 2010/0172556        to Cohen, and/or US 2010/0228076 to Blank, all of which        applications are incorporated herein by reference.    -   7. A healthcare professional indicates a location of the guiding        catheter on the angiographic image (e.g., using user interface        13).    -   8. The geometry-indication-receiving functionality 14 of the        processor utilizes the known dimensions of the guiding catheter        to calibrate dimensions that are measured in the angiographic        image, for example, in accordance with techniques described in        WO 10/058398 to Cohen, US 2010/0172556 to Cohen, and/or US        2010/0228076 to Blank, all of which applications are        incorporated herein by reference. For some applications,        alternative techniques are used for calibrating the dimensions        that are measured in the angiographic image. For some        applications, techniques as described in International Patent        Application PCT/IL2013/050438 (published as WO 13/175472), which        is incorporated herein by reference, are used for calibrating        the dimensions that are measured in the image.    -   9. A healthcare professional indicates a location of the        stenosis on the angiographic image (e.g., using user interface        13). For some applications, processor 10 identifies the location        of a stenosis at least partially automatically, for example, in        accordance with techniques described in WO 10/058398 to Cohen,        US 2010/0172556 to Cohen, and/or US 2010/0228076 to Blank, all        of which applications are incorporated herein by reference. For        example, a user may designate a single location in an image that        is at or near a given location of a given blood lumen in the        image (e.g., using user interface 13). In response to the user        designating the single location, the system automatically        detects a stenosis in the vicinity. For example, the system may        identify edge lines and the reference diameters of the stenosis.    -   10. Quantitative measurements of the lumen geometry (e.g., QCA        measurements) are performed by geometry-indication-receiving        functionality 14. For some applications, QCA measurements are        performed automatically and/or in real time or near real time,        for example, in accordance with techniques described in WO        10/058398 to Cohen, US 2010/0172556 to Cohen, and/or US        2010/0228076 to Blank, all of which applications are        incorporated herein by reference. For some applications, one or        more of the following steps are performed automatically by the        geometry-indication-receiving functionality, in order to perform        the QCA measurements:        -   a. The lumen is enhanced, for example, in accordance with            techniques described in WO 10/058398 to Cohen, US            2010/0172556 to Cohen, and/or US 2010/0228076 to Blank, all            of which applications are incorporated herein by reference.        -   b. A vesselness index of pixels of the image is calculated,            for example, in accordance with techniques described in WO            10/058398 to Cohen, US 2010/0172556 to Cohen, and/or US            2010/0228076 to Blank, all of which applications are            incorporated herein by reference.        -   c. Centerlines of lumens are automatically determined, for            example, in accordance with techniques described in WO            10/058398 to Cohen, US 2010/0172556 to Cohen, and/or US            2010/0228076 to Blank, all of which applications are            incorporated herein by reference.        -   d. Edges of lumens are automatically detected, for example,            in accordance with techniques described in WO 10/058398 to            Cohen, US 2010/0172556 to Cohen, and/or US 2010/0228076 to            Blank, all of which applications are incorporated herein by            reference.        -   e. Measurements of the lumen geometry are made            automatically, for example, in accordance with techniques            described in WO 10/058398 to Cohen, US 2010/0172556 to            Cohen, and/or US 2010/0228076 to Blank, all of which            applications are incorporated herein by reference.    -   11. Blood-velocity-determination functionality 16 of processor        10 defines at least two regions of interest, typically along the        lumen center line. For some applications, three or more regions        of interest are selected, the regions of interest typically        being equidistant from each other along the center line.    -   12. The lumen is tracked through at least a portion of, and        typically through the entire, angiographic sequence. For some        applications, the lumen is automatically identified in the        angiographic images and the images are aligned with respect to        each other by aligning the lumen in the images, for example, in        accordance with techniques described in US 2008/0221442 to        Tolkowsky, WO 10/058398 to Cohen, US 2010/0172556 to Cohen,        and/or US 2010/0228076 to Blank, all of which applications are        incorporated herein by reference. For some applications, in        order to align the images with respect to each other, the shape        of the lumen in some of the images is warped. For example, the        warping may be applied by determining a transformation function        for transforming locations within the lumen (such as the regions        of interest) in respective images with respect to each other,        for example, in accordance with techniques described in WO        10/058398 to Cohen, US 2010/0172556 to Cohen, and/or US        2010/0228076 to Blank, all of which applications are        incorporated herein by reference. For some applications, a        transformation function is determined using techniques as        described in International Patent Application PCT/IL2013/050438        (published as WO 13/175472), which is incorporated herein by        reference.    -   13. Blood-velocity-determination functionality 16 of processor        10 identifies the regions of interest within all of the image        frames of the angiographic sequence. Typically, the alignment of        the image frames with each other, and/or the determination of        transformation functions (for transforming locations within the        lumen (such as the regions of interest) in respective images        with respect to each other), as performed in step 12,        facilitates the identification of the regions of interest within        the image frames of the angiographic sequence.    -   14. Blood-velocity-determination functionality 16 of processor        10 estimates the velocity of the contrast agent through the        coronary artery using time-density curves and/or contrast flow        maps. The blood-velocity-determination functionality typically        determines the blood velocity by determining that a point (e.g.,        a peak) of the time-density curve moved from a first region of        interest to an adjacent region of interest between first and        second (not necessarily adjacent) angiographic image frames. The        time taken for the contrast agent to move from the first region        of interest to the second region of interest may be determined        by determining the period of time that separated the acquisition        of the first image frame and the acquisition of the second image        frame. For some applications, the time taken for a bolus of        contrast agent, a given concentration of contrast agent, and/or        a pattern of contrast agent to move from the first region of        interest to the second region of interest is determined. The        distance between the first region of interest and the second        region of interest may be determined by determining the distance        between the first region of interest and the second region of        interest in the image frame that was selected in step 6, the        distance being calibrated based upon the known dimensions of the        guiding catheter, in accordance with step 8.    -   15. Processor 10 calculates hyperemic coronary flow, based upon        the QCA and the blood velocity calculations.    -   16. The pressure drop due to the stenosis is calculated, based        upon the determined hyperemic flow, in accordance with the        techniques described herein.    -   17. Aortic pressure is received by        flow-related-parameter-receiving functionality 19. For some        applications, a healthcare professional manually inputs the        aortic pressure, for example, based upon the pressure detected        by an aortic pressure sensor. Alternatively or additionally, the        processor automatically receives the aortic pressure from an        aortic pressure sensor.    -   For some applications, as an alternative to receiving the        subject's aortic pressure, the        flow-related-parameter-determination functionality receives an        indication of a parameter that is indicative of a flow-related        parameter within the subject's lumen while the subject was        healthy, by receiving data relating to the subject's patient        history. For example, the processor may receive at least one        angiographic image of the subject's lumen that was acquired at a        time when the subject was healthy, as described hereinbelow. The        processor may derive flow within the lumen or blood velocity        within the lumen at the time of the acquisition of the        previously-acquired image (i.e., at the time when the lumen was        healthy), by performing image processing on the        previously-acquired image. Alternatively or additionally, the        flow-related-parameter-determination functionality receives an        angiographic image of a second location within the lumen, and a        flow-related parameter (such as pressure, flow, or blood        velocity) at the second location within the lumen is determined        by performing image-processing on the angiographic image of the        second location. For example, the geometry of the lumen at the        second location may be determined using the techniques described        herein, and blood pressure, blood velocity and/or flow at the        second location may thereby be determined, using the techniques        described herein.    -   18. Index-determination functionality calculates FFR and/or        another luminal-flow-related index based upon the aortic        pressure and the calculated pressure drop, in accordance with        the techniques described herein. Alternatively or additionally,        index-determination functionality calculates FFR and/or another        luminal-flow-related index by comparing current flow or blood        velocity in the vicinity of the stenosis to flow or blood        velocity within the lumen at a time when the lumen was healthy,        in accordance with the techniques described herein. Further        alternatively or additionally, the luminal flow-related index is        determined by comparing the value of the current flow-related        parameter at the location of interest to the value of the        flow-related parameter at the second location.

For some applications, the techniques described herein are applied to alumen that defines a second stenosis that is downstream of a firststenosis. For some such applications, in order to determine aluminal-flow-related index of the second stenosis, the processordetermines the luminal pressure at a site between the first stenosis andthe second stenosis, and uses this pressure as the pressure to which thepressure downstream of the second stenosis is compared. Alternatively,in order to determine the luminal-flow-related index of the secondstenosis, the processor uses the aortic pressure as the pressure towhich the pressure downstream of the second stenosis is compared.

The following portion of the present application describes modelsaccording to which parameters that are derived from angiogram data areused in order to calculate a luminal-flow-related index (e.g., FFR), inaccordance with some applications of the present invention. Typicallysuch steps are performed by index-determination functionality 21 ofprocessor 10.

For some applications of the current invention, FFR, and/or anotherluminal-flow-related index is deduced from data that are typicallyderived from the angiogram. For some applications, such parametersinclude the geometry of the lumen, the aortic pressure, the density ofthe contrast agent as observed in the angiogram images, the hyperemicflow, and/or the density and viscosity of blood. It is noted thattypically, blood velocity and lumen geometry are determined solely byperforming image processing on the two-dimensional angiographic images.Further typically, blood velocity and lumen geometry are determinedwithout generating a three-dimensional model of the lumen. For someapplications, such parameters are derived using one or more of thefollowing techniques:

-   -   For some applications, the geometry of the lumen is determined,        typically online and typically in response to a single user        click, at the area of the stenosis, e.g., by performing QCA. As        described hereinabove, QCA may be performed using images that        were acquired from two or more viewing angles.    -   For some applications, aortic pressure P_(a) is measured through        the guiding catheter, as described hereinabove.    -   For some applications, geometry-indication-receiving        functionality 14 determines the cross-sectional area of the        lumen in the vicinity of the stenosis, and/or at other locations        along the lumen (e.g., within a healthy portion of the lumen),        by performing densitometry on at least one of the angiographic        images, in accordance with the techniques described hereinbelow.        For some applications, densitometry is performed, typically        automatically, by comparing the density of the contrast agent in        a healthy section of the lumen (e.g., the section proximal to        the stenosis) to the density of the contrast agent in other        parts of the lumen (e.g., in the vicinity of the stenosis, or        downstream of the stenosis). For some applications, such a        comparison is made on an angiogram image after background        subtraction is applied to the angiogram image. For some        applications, background subtraction is performed by subtracting        images acquired before the contrast injection from images        acquired after the contrast injection. For some applications,        the images acquired before the contrast injection and the images        acquired after the contrast injection are gated to the same        phase in the cardiac cycle. For some applications, the images        acquired before the contrast injection and the images acquired        after the contrast injection are gated to the end-diastolic        phase.    -   For some applications, the hyperemic flow is calculated by        digital subtraction angiography, for example using techniques        that are similar to those described in one or more of the        following references, which are incorporated herein by        reference:        -   Molloi, S., Ersahin, A., Tang, J., Hicks, J. & Leung, C. Y.,            1996 “Quantification of volumetric coronary blood flow with            dual-energy digital subtraction angiography,” Circulation            93, 1919-1927;        -   Molloi, S., Zhou, Y. & Kassab, G. S. 2004 “Regional            volumetric coronary blood flow measurement by digital            angiography: in vivo validation,” Acad. Radiol. 11, 757-766;        -   Sabee Molloi, David Chalyan, Huy Le and Jerry T. Wong, 2012,            “Estimation of coronary artery hyperemic blood flow based on            arterial lumen volume using angiographic images,” The            International Journal Of Cardiovascular Imaging, Volume 28,            Number 1, 1-11; and        -   Molloi S, Bednarz G, Tang J, Zhou Y, Mathur T (1998),            “Absolute volumetric coronary blood flow measurement with            digital subtraction angiography,” Int J Card Imaging            14:137-145.    -   For some applications, the hyperemic flow is calculated by        performing digital subtraction on images of the stenosis or        lumens, which have been stabilized via image tracking, with or        without warping of the lumens in the images, e.g., using        techniques described hereinabove. For some applications, flow is        determined in accordance with techniques described in US        2008/0221442 to Tolkowsky, which is incorporated herein by        reference. For example, on-line geometric and/or hemodynamic        measurements (e.g., size, flow, ejection fraction) may be made        and/or displayed upon stabilized images, e.g., as described with        reference to FIG. 4. Alternatively or additionally, a stabilized        image stream may be used for on-line measurement of the flow        within a lumen, e.g., by measuring the time it takes a presence        of contrast agent (e.g., a bolus of contrast agent, a given        concentration of contrast agent, and/or a pattern of contrast        agent) to travel a known distance, in accordance with the        techniques described hereinabove.    -   For some applications, the hyperemic flow is calculated by        multiplying blood velocity, by the lumen cross-sectional area,        the blood velocity and the lumen cross-sectional area typically        having been determined automatically by processor 10.    -   For some applications, blood velocity is calculated from        angiogram images by comparing density curves, for example, as        described hereinabove with reference to FIG. 3B, and/or as        described in Gerhard Albert ten Brinke, 2011, “Automated        coronary flow reserve assessment using planar x-ray        angiography”, PhD dissertation, Universiteit Twente, chapter 3        (hereinafter “ten Brinke”), which is incorporated herein by        reference.    -   For some applications, the blood velocity is calculated from        angiogram images by using contrast flow maps, e.g., using        techniques that are similar to those described in ten Brinke,        which is incorporated herein by reference.    -   For some applications, the cross-sectional area is calculated        from QCA measurements of the artery and/or by densitometry.    -   For some applications, the density and/or viscosity of blood is        determined, for example, using techniques described in one or        more of the following references, which are incorporated herein        by reference:        -   Gerald E. Miller, “Fundamentals of Biomedical Transport            Processes, Morgan & Claypool Publishers,” chapter 2; and        -   Buddy D. Ratner, “Biomaterials Science: An Introduction to            Materials in Medicine,” Elsevier, chapter 7.

The following is a description of how FFR is calculated, utilizing atleast some of the above-mentioned parameters, the parameters typicallyhaving been determined automatically from one or more angiographicimages, in accordance with some applications of the present invention.

As described hereinabove, mathematically, FFR is defined as:FFR=P _(d) /P _(a)=(P _(a) −ΔP _(s))/P _(a)

Assuming there is no disease in the lumen proximal to the stenosis inquestion, the value of the proximal pressure P_(a) may be assumed to bethe same as the aortic pressure. Therefore, typically, processor 10assumes that the pressure proximal to the stenosis is equal to themeasured aortic pressure. For some applications, in order to calculateFFR, the processor calculates the pressure drop in the stenotic part ofthe lumen, i.e., ΔP_(s).

For some applications, the calculation of ΔP_(s) is performed by usingthe Bernoulli equation, e.g., using generally similar techniques tothose described in Yunlong Huo, Mark Svendsen, Jenny Susana Choy, Z.-D.Zhang and Ghassan S. Kassab, 2011, “A validated predictive model ofcoronary fractional flow reserve,” J. R. Soc. Interface (hereinafter“Huo”), which is incorporated herein by reference. For someapplications, the system applies the Bernoulli equation, while ignoringthe effect of gravity in the coronary circulatory system, such that theBernoulli equation can be written as follows:ΔP _(s) =ΔP _(convective) +ΔP _(constriction) +ΔP _(diffusive) +ΔP_(expansion)

Each element of the pressure drop in the above equation is a function ofthe lumen geometry (e.g., lengths and cross-sections), the hyperemicflow rate in the lumen segment and the density and viscosity of blood,all of which parameters may be determined automatically fromangiographic images of the lumen, in accordance with techniquesdescribed herein. Thus, for some applications, the value of the pressuredrop is calculated using the aforementioned parameters.

For some applications, the pressure drop is calculated in a generallysimilar manner to that described in Huo, but using parameters that areautomatically determined based upon angiographic images of the lumen, asdescribed hereinabove.

For some applications, FFR and/or another luminal-flow-related index, isdetermined by processor 10 generating a local model of a portion of thelumen, using a combination of QCA and densitometry data obtained fromangiogram images.

The following is a description of how FFR may be calculated, utilizingthe above-mentioned data.

FFR is defined as:FFR=P _(d) /P _(a)

Assuming there is no disease in the lumen proximal to the stenosis inquestion, the value of the proximal pressure P_(a) may be assumed to bethe same as the aortic pressure. For some applications, aortic pressureis measured through the guiding catheter, as described hereinabove.

What remains, in order to calculate FFR, is to calculate the pressuredistal to the stenotic part of the lumen, i.e., P_(d).

For some applications the pressure distal to the stenotic portion of thelumen is determined by the processor as follows:

-   -   1) An angiogram is performed under hyperemic conditions.    -   2) QCA and densitometry are performed on the stenotic portion        and in the vicinity thereof. As described hereinabove, for some        applications, QCA is performed using images acquired from two or        more viewing angles.    -   3) One or more of the following boundary conditions are        determined:        -   a. coronary blood flow;        -   b. proximal blood pressure; and        -   c. proximal blood velocity.    -   4) Computational fluid dynamics equations are solved, using the        aforementioned parameters as inputs, in order to obtain the        pressure distal to the stenotic part of the lumen, i.e., P_(d).        For some applications, the Navier-Stokes equations listed below        are solved, using the aforementioned parameters as inputs, in        order to obtain the pressure distal to the stenotic part of the        lumen:        ∂p/∂t+∂/∂x _(j)[ρu _(j)]=0        ∂/∂t(ρu _(i))+∂/∂x _(j)[ρu _(i) u _(j)+ρδ_(ij)−τ_(ji)]=0,i=1,2,3        ∂/∂t(ρe ₀)+∂/∂x _(j)[ρu _(j) e ₀ +u _(j) p+q _(j) +u        _(i)τ_(ji)]=0

For some applications, FFR is deduced by solving the computational fluiddynamics equations, which are dependent on data that is typicallyavailable in the angiogram. For some applications, such parametersinclude the geometry of the coronary vessel, the geometry of thestenosis, the aortic pressure, the density of the contrast agent asobserved in the angiogram images, the hyperemic flow, and the densityand viscosity of blood. For some applications, such parameters arederived using one or more of the following techniques:

-   -   For some applications, the geometric model of the stenosis is        obtained by extrapolating lumen measurement data from QCA. For        some applications, the geometry of the lumen is determined,        typically online and typically in response to a single user        click, at the area of the stenosis, e.g., by performing QCA. As        described hereinabove, QCA may be performed using images that        were acquired from two or more viewing angles.    -   For some applications, densitometry is used to determine or to        enhance the accuracy of the geometric model of the stenosis. For        some applications, geometry-indication-receiving functionality        14 determines the cross-sectional area of the lumen in the        vicinity of the stenosis, and/or at other locations along the        lumen (e.g., within a healthy portion of the lumen) by        performing densitometry on at least one of the angiographic        images, in accordance with the techniques described hereinbelow.        For some applications, densitometry is obtained, typically        automatically, by comparing the density of the contrast agent in        a healthy section of the lumen (e.g., the section proximal to        the stenosis) to its density in other parts of the lumen (e.g.,        in the vicinity of the stenosis, or downstream of the stenosis).        For some applications, such a comparison is made on an angiogram        image after background subtraction is applied to the angiogram        image. For some applications background subtraction is performed        by subtracting images acquired before the contrast injection        from images acquired after the contrast injection. For some        applications, the images acquired before the contrast injection        and the images acquired after the contrast injection are gated        to the same phase in the cardiac cycle. For some applications,        the images acquired before the contrast injection and the images        acquired after the contrast injection are gated to the        end-diastolic phase.    -   For some applications, the hyperemic flow is calculated by        digital subtraction angiography, for example, using techniques        that are similar to those described in one or more of the        following references, which are incorporated herein by        reference:        -   Molloi, S., Ersahin, A., Tang, J., Hicks, J. & Leung, C. Y.,            1996 “Quantification of volumetric coronary blood flow with            dual-energy digital subtraction angiography,” Circulation            93, 1919-1927;        -   Molloi, S., Zhou, Y. & Kassab, G. S. 2004 “Regional            volumetric coronary blood flow measurement by digital            angiography: in vivo validation,” Acad. Radiol. 11, 757-766;        -   Sabee Molloi, David Chalyan, Huy Le and Jerry T. Wong, 2012,            “Estimation of coronary artery hyperemic blood flow based on            arterial lumen volume using angiographic images,” The            International Journal Of Cardiovascular Imaging, Volume 28,            Number 1, 1-11; and        -   Molloi S, Bednarz G, Tang J, Zhou Y, Mathur T (1998),            “Absolute volumetric coronary blood flow measurement with            digital subtraction angiography,” Int J Card Imaging            14:137-145    -   For some applications, the hyperemic flow is calculated by        performing digital subtraction on images of the stenosis or        lumens, which have been stabilized via image tracking, with or        without warping of the lumens in the images, e.g., using        techniques described hereinabove. For some applications, flow is        determined in accordance with techniques described in US        2008/0221442 to Tolkowsky, which is incorporated herein by        reference. For example, on-line geometric and/or hemodynamic        measurements (e.g., size, flow, ejection fraction) may be made        and/or displayed upon the stabilized images, e.g., as described        with reference to FIG. 4. Alternatively or additionally, a        stabilized image stream may be used for on-line measurement of        the flow within a lumen, e.g., by measuring the time it takes a        presence of contrast agent (e.g., a bolus of contrast agent, a        given concentration of contrast agent, and/or a pattern of        contrast agent) to travel a known distance, in accordance with        the techniques described hereinabove.    -   For some applications, the hyperemic flow is calculated by        multiplying blood velocity by the lumen cross-sectional area,        the blood velocity and the lumen cross-sectional area typically        having been determined automatically by processor 10.    -   For some applications, the blood velocity is calculated from        angiogram images by comparing density curves, for example, as        described hereinabove with reference to FIGS. 3A-B, and/or as        described in ten Brinke, which is incorporated herein by        reference.    -   For some applications, the blood velocity is calculated from        angiogram images by using contrast flow maps, e.g., using        techniques that are similar to those described in ten Brinke,        which is incorporated herein by reference.    -   For some applications, the cross-sectional area is calculated        from QCA measurements of the artery and/or densitometry.    -   For some applications, the density and viscosity of blood is        determined, for example, using techniques that are similar to        those described in one or more of the following references,        which are incorporated herein by reference:        -   Gerald E. Miller, “Fundamentals of Biomedical Transport            Processes, Morgan & Claypool Publishers,” chapter 2; and        -   Buddy D. Ratner, “Biomaterials Science: An Introduction to            Materials in Medicine,” Elsevier, chapter 7.

As described hereinabove, typically, parameters relating to the geometryof the lumen, and/or flow within the lumen are determined fromangiographic images of the lumen. For some applications, aluminal-flow-related index (e.g., FFR) is calculated, in whole or inpart, using a model which was previously created by means of a machinelearning classifier (e.g., Support Vector Machine, Neural Network,etc.). Typically, in order to train the machine learning classifier, FFRor a similar luminal-flow-related index of a blood vessel is measuredusing conventional methods (e.g., using a pressure wire, and/or analternative technique). Additionally, angiographic images of the bloodvessel are acquired, and are analyzed such as to determine parameterssuch as lumen dimensions, blood velocity, blood flow, haziness, heartmuscle flush, time of contrast dissipation, densitometry, QCA, distancefrom an ostium, number of bifurcations between an ostium and a lesion,and/or anatomical locations (e.g., distal left anterior descendingartery, proximal right coronary artery, 5 mm along the circumflexbranch, etc.). Feature vectors consisting of some, or all of, the abovementioned parameters are derived from the angiograms. Multiple sets ofthe aforementioned vectors, together with the corresponding measuredFFR, and/or other measured luminal-flow-related indices, are provided asinputs to the machine learning classifier. For some applications, theaforementioned FFR and/or other luminal-flow-related index is quantized,such as to allow multiclass classification for each discrete level ofFFR and/or other luminal-flow-related index. For some applications, amachine learning algorithm which allows a continuous result function(e.g. a machine learning regression algorithm) is used to train amachine learning classifier using the FFR or other luminal-flow-relatedindex inputted into the algorithm as is, i.e., without the FFR or theother luminal-flow-related index being quantized.

After training the aforementioned machine learning classifier, asubject's FFR and/or other luminal-flow-related input parameter isderived, using the machine learning classifier, using an angiogram of alumen of the subject. At least some of the parameters that areautomatically derived from an angiogram of a lumen of the subject areprovided as inputs to the machine learning classifier. Based on thetraining of the machine learning classifier, the classifier uses theparameters that are inputted to the classifier to predict FFR or anotherluminal-flow-related index. Typically, the classifier predicts FFR oranother luminal-flow-related index, by determining one or more featurevectors of the blood vessel based upon the inputted parameters, and byutilizing the data collected and processed by the classifier during theaforementioned training phase to determine the luminal-flow-relatedindex based upon the feature vector(s).

For some applications, the value of the current flow-related parameterat a location within a lumen is determined using a machine-learningclassifier, based upon at least the determined blood velocity and thegeometry of the lumen at the location. For some applications, the valueof the luminal-flow-related index is determined by determining therelationship between the value of a current flow-related parameter andthe value of a second flow-related parameter, using a machine-learningclassifier.

For some applications of the current invention, a luminal-flow-relatedindex (e.g., FFR) is deduced, using patient history as an input, inaccordance with the following technique.

FFR is defined as the ratio between stenotic flow Q_(S) and normal flowQ_(N) under hyperemic conditions: FFR=Q_(S)/Q_(N).

For some applications, patient history data (typically, data obtainedusing a cine angiogram injection post treatment of a stenosis) areanalyzed in order to determine the subject's normal flow through thelumen (i.e., the subject's flow through the lumen, when the subject washealthy). For example, the subject's normal flow may be determined byanalyzing a historical angiographic image sequence of the subject, usingthe techniques described hereinabove. The subject's stenotic flowthrough the lumen is determined by analyzing an angiographic sequenceacquired while the subject had the stenosis (e.g., a currentangiographic image sequence), in accordance with the techniquesdescribed hereinabove. A luminal-flow-related index (e.g., FFR), isdetermined by comparing to each other the normal and the stenotic flows.

For some applications, the coronary flow is calculated by applyingdensitometry to digital subtraction angiography images, for example,using techniques described in one or more of the following references,which are incorporated herein by reference:

-   -   Molloi, S., Ersahin, A., Tang, J., Hicks, J. & Leung, C. Y.,        1996 “Quantification of volumetric coronary blood flow with        dual-energy digital subtraction angiography,” Circulation 93,        1919-1927;    -   Molloi, S., Zhou, Y. & Kassab, G. S. 2004 “Regional volumetric        coronary blood flow measurement by digital angiography: in vivo        validation,” Acad. Radiol. 11, 757-766;    -   Sabee Molloi, David Chalyan, Huy Le and Jerry T. Wong, 2012,        “Estimation of coronary artery hyperemic blood flow based on        arterial lumen volume using angiographic images,” The        International Journal Of Cardiovascular Imaging, Volume 28,        Number 1, 1-11; and    -   Molloi S, Bednarz G, Tang J, Zhou Y, Mathur T (1998), “Absolute        volumetric coronary blood flow measurement with digital        subtraction angiography,” Int J Card Imaging 14:137-145.

For some applications, the coronary flow is calculated by performingdigital subtraction on images of the stenosis or lumens, which have beenstabilized via image tracking, with or without warping of the lumens inthe images, e.g., using techniques described hereinabove. For someapplications, flow is determined in accordance with techniques describedin US 2008/0221442 to Tolkowsky, which is incorporated herein byreference. For example, on-line geometric and/or hemodynamicmeasurements (e.g., size, flow, ejection fraction) may be made and/ordisplayed upon the stabilized images, e.g., as described with referenceto FIG. 4. Alternatively or additionally, a stabilized image stream maybe used for on-line measurement of the flow within a lumen, e.g., bymeasuring the time it takes a presence of contrast agent (e.g., a bolusof contrast agent, a given concentration of contrast agent, and/or apattern of contrast agent) to travel a known distance, in accordancewith the techniques described hereinabove.

For some applications of the current invention, a luminal-flow-relatedindex (e.g., FFR) is deduced, using patient history as an input, inaccordance with the following technique.

FFR is defined as the ratio of stenotic flow Q_(S) and normal flowQ_(N). In turn, the flow can be written as the product of mean velocityand volume, divided by length L, of a lumen segment.FFR=(Q _(S) /Q_(N))=((VELOCITY_(S))(VOLUME_(S))/L)/((VELOCITY_(N))(VOLUME_(N))/L)

For some applications, patient history data (typically, data obtainedusing a cine angiogram injection post treatment of a stenosis), areanalyzed in order to determine the subject's normal blood velocitywithin the lumen (i.e., the subject's blood velocity within the lumen,when the subject was healthy). For example, the subject's normal bloodvelocity may be determined by analyzing a historical angiographic imagesequence, using the techniques described hereinabove. The subject'sstenotic blood velocity is determined by analyzing an angiographicsequence acquired while the subject had the stenosis (e.g., a currentangiographic image sequence), in accordance with the techniquesdescribed hereinabove. This provides both normal and stenotic bloodvelocities, thus facilitating the calculation of the FFR.

The FFR is typically determined by identifying a segment of the lumenthat is currently healthy (even though the lumen currently contains astenosis in a different segment thereof). A ratio is determined betweenthe blood velocity in the segment of the lumen at the time of theacquisition of the historical angiographic image sequence (when thewhole lumen was healthy), and blood velocity in a healthy segment of thestenotic lumen at the time of the acquisition of the currentangiographic sequence. Assuming that the volume of the segment of thelumen being analyzed is substantially unchanged between the time of theacquisition of the historical angiographic image sequence and the timeof the acquisition of the current angiographic sequence, the ratio offlows is equal to the ratio of the velocities in this segment. Thus:FFR=(Q _(S) /Q _(N))=VELOCITY_(S)/VELOCITY_(N)

For some applications, the blood velocity is calculated from angiogramimages by comparing density curves, for example, as describedhereinabove with reference to FIGS. 3A-B, and/or as described in tenBrinke, which is incorporated herein by reference.

For some applications, the blood velocity is calculated from angiogramimages by using contrast flow maps, for example, using techniques asdescribed in ten Brinke, which is incorporated herein by reference.

Reference is now made to FIG. 5, which is a schematic illustration of aprocessor 50 that is used to determine a characteristic of a lumen bymeans of image processing, in accordance with some applications of thepresent invention. Typically the processor determines the characteristicof the lumen based upon image processing of angiographic images of thelumen that are acquired by an imaging device 51. Processor 50 typicallyreceives inputs via the imaging device and via a user interface 52, andgenerates an output on display 53. The imaging device, the userinterface, and the display are generally similar to those described withreference to FIG. 1. For some applications, functionalities describedwith reference to processor 50 are performed in conjunction withfunctionalities performed with one or more of the other processorsdescribed herein.

For some applications of the present invention, image-processingfunctionality 54 of processor 50 analyzes temporal changes in a densityof a contrast agent at a given location within the lumen, within anangiographic sequence of the lumen. In response to the analysis,lumen-characterization functionality 55 determines a characteristic ofthe lumen at the location. For example, contrast agent may beadministered to the lumen in accordance with a protocol. For example, asdescribed hereinabove, an automated injection device may be programmedto inject pulses of contrast agent in a predetermined pattern, e.g., ina pattern having a given time-density curve. For some applications, theprocessor compares (a) the temporal changes in the density of thecontrast agent at the location within the lumen to (b) the protocol inaccordance with which the contrast agent was administered. The processordetermines a characteristic of the lumen at the location in response tothe comparison. For example, in response to seeing that there is abuild-up of contrast agent at the location, the processor may determinethat there is a stenosis in the vicinity of the location, e.g., at thelocation, upstream of the location, and/or downstream of the location.For some applications, based upon temporal changes in the density of acontrast agent at the given location, the lumen-characterizationfunctionality determines a luminal-flow-related index (e.g., FFR) of thelumen at the location. For some applications, the lumen-characterizationfunctionality determines the characteristic of the lumen, based upon thetemporal changes in the density of the contrast agent, using a machinelearning classifier. For some applications, the processor includesgeometry-indication-receiving functionality 56, which is configured todetermine the geometry of the lumen at the location in a generallysimilar manner to that described with respect to thegeometry-indication-receiving functionality described with reference toFIG. 1. The luminal-flow-related index is determined at least partiallybased upon the geometry of the lumen at the location. Output-generationfunctionality 57 generates an output on the display in response to thedetermined characteristic of the lumen.

Calculating Flow Velocities from Angiograms and Using the FlowVelocities to Calculate a CFR Measure

Coronary flow reserve (CFR) is defined as the ratio between hyperemicblood velocity and resting blood velocity. For some applications, afirst angiogram is acquired under hyperemic conditions, and a secondangiogram is acquired under resting conditions. The velocity of bloodflow in the selected lumen is automatically determined in the first andsecond angiogram images (e.g., using techniques described hereinabove),and the determined velocities are used to calculate the CFR.

For some applications, the blood velocity is calculated from angiogramimages by comparing density curves, for example, as describedhereinabove with reference to FIGS. 3A-B, and/or as described in tenBrinke, which is incorporated herein by reference.

For some applications, the blood velocity is calculated from angiogramimages by using contrast flow maps, for example, as described in tenBrinke, which is incorporated herein by reference.

Calculating Lumen Dimensions and Geometry (QCA) from ActualVelocity/Pressure Readings

Reference is now made to FIG. 6, which is a schematic illustration of aprocessor 60 that is used to calculate lumen dimensions and/or lumengeometry based upon blood velocity and pressure measurement, inaccordance with some applications of the present invention. Typically,the processor calculates lumen dimensions based upon (a) pressure withinthe lumen measured by a pressure sensor 61, and (b) blood velocitywithin the lumen, measured by a blood velocity sensor 62. For someapplications, the pressure sensor and blood velocity sensor are coupledto a tool 63 that is configured to be inserted into the lumen. For someapplications, functionalities described with reference to processor 60are performed in conjunction with functionalities performed with one ormore of the other processors described herein.Lumen-dimension-derivation functionality 64 of the processor derives adimension of the lumen from the measured pressure and blood velocity.Output-generation functionality 65 generates an output on a display 66in response to the derived dimension.

For some applications, the blood velocity and pressure readings aregathered simultaneously, for example, using a device that is capable ofmeasuring blood pressure and blood velocity simultaneously in a lumen,while the device is being moved through the lumen (e.g., during pullbackof the device through the lumen). For example, the ComboWire®manufactured by Volcano Corp. (San Diego, Calif.) may be used to measureblood pressure and blood velocity simultaneously.

For some applications, the lumen cross-sectional areas and length areautomatically calculated by solving computational fluid dynamicsequations, which are dependent on the velocity and pressure values alongthe lumen segment. Alternatively or additionally, a length of a portionof the lumen, a diameter of the lumen, a minimal lumen diameter of thelumen, and/or a percentage occlusion of the lumen is determined.

For some applications, in a circular stenosis the length andcross-sections of the lumen are calculated based upon the followingequations:

$Q = \frac{\mathbb{d}P}{\mathbb{d}R}$$L = {\frac{Q}{8{\pi\eta}}{\int_{t_{0}}^{t_{1}}\frac{P^{\prime}{\mathbb{d}t}}{v^{2}}}}$Q = vA ${\mathbb{d}R} = \frac{8\eta{\mathbb{d}L}}{\pi\; r^{4}}$$A = \frac{Q}{v}$

where L is the length of at least a portion of a segment of a lumenalong which pullback is performed, A is the cross-sectional area alongthe lumen, v is the blood velocity along the lumen as measured by thedevice, Q is the blood flow, η is the blood viscosity, P′ is the timederivative of the pressure along the lumen as measured by the device, ris the radius of the lumen, and t₀ and t₁ are the times at which thedevice is at respective ends of the luminal segment during the pullback.

Co-Registration of Endoluminal Images and Extraluminal Images

Reference is now made to FIG. 7, which is a schematic illustration of aprocessor 70 that is used to co-register at least some of theendoluminal data points to locations along the lumen within anextraluminal image, in accordance with some applications of the presentinvention. Processor 70 typically receives inputs via imaging device 71,data-acquisition device 72, and a user interface 73, and generates anoutput on display 74. Typically, the processor receives extraluminalimages of the lumen that are acquired by an extraluminal imaging device71. Further typically, the processor receives endoluminal data points ofthe lumen that are acquired by an endoluminal data-acquisition device72. The extraluminal imaging device, the user interface, and the displayare typically generally similar to those described with reference toFIG. 1. For some applications, functionalities described with referenceto processor 70 are performed in conjunction with functionalitiesperformed with one or more of the other processors described herein.

Typically, processor 70 includesendoluminal-geometry-derivation-functionality 75, which is configured,for at least some of the endoluminal data points, to derive from theendoluminal data point a value of a geometrical parameter of the lumen(e.g., cross-sectional area of the lumen, and/or a diameter of thelumen) at a location within the lumen at which the endoluminal datapoint was acquired. Further typically, processor 70 includesextraluminal-geometry-derivation-functionality 76, which is configuredto derive values of the geometrical parameter of the lumen (e.g.,cross-sectional area of the lumen, and/or a diameter of the lumen) at aplurality of locations along the lumen, by performing image processingon the at least one extraluminal image of the lumen (e.g., usingtechniques described hereinabove). Co-registration functionality 77 ofthe processor is configured to co-register at least some of theendoluminal data points to locations along the lumen within theextraluminal image by correlating (a) the values of the geometricalparameters (e.g., a sequence of values of the geometrical parameters)corresponding to the endoluminal data points with (b) the values of thegeometrical parameter (e.g., a sequence of values of the geometricalparameters) determined by performing image processing on the at leastone extraluminal image. For some applications, the co-registrationfunctionality correlates (a) a variation (e.g., a mathematicalderivative) of the values of the geometrical parameter corresponding toa sequence of endoluminal data points with (b) a variation (e.g., amathematical derivative) of the values of the geometrical parametercorresponding to a sequence of locations within the extraluminal image.Output-generation functionality 78 of the processor generates an outputon the display based upon the co-registration (e.g., an outputindicating that a given endoluminal data point corresponds to a givenlocation along the lumen).

For some applications, the endoluminal data-acquisition device acquiresendoluminal images, and endoluminal-geometry-derivation-functionality 75derives the value of the geometrical parameter of the lumen at thelocation within the lumen at which an endoluminal image was acquired byperforming image processing on the endoluminal image. Alternatively oradditionally, the endoluminal data-acquisition device acquires bloodvelocity, flow, and/or blood pressure data points, andendoluminal-geometry-derivation-functionality 75 derives the value ofthe geometrical parameter of the lumen from the blood velocity, flow,and/or blood pressure data points, e.g., using techniques describedhereinabove.

For some applications, processor 70 includes index-determinationfunctionality 79 (and/or other functionalities described with referenceto FIG. 1), and the processor is configured to determine aluminal-flow-related index of the subject in a non-invasive manner,e.g., using techniques described hereinabove. By performing theco-registration, it is determined that respective endoluminal datapoints correspond to respective values of the luminal flow-relatedindex. The output-generation functionality generates an output on thedisplay based upon determining that respective endoluminal data pointscorrespond to respective values of the luminal flow-related index (e.g.,by generating an output indicating that a given endoluminal data pointcorresponds to a given value of the luminal flow-related index).

For some applications, the endoluminal data-acquisition device, whilebeing moved through the lumen, acquires endoluminal data points (e.g.,endoluminal images (such as IVUS images or OCT images), or functionalendoluminal data points) in addition to acquiring blood velocity data(e.g., using a velocity sensor that is coupled to the endoluminaldata-acquisition device). Typically, the endoluminal data acquisitiondevice, while being moved through the lumen, acquires a set of theendoluminal data points, and a set of blood velocity data points, theblood velocity data points being indicative of the blood velocity withinthe lumen (and therefore being indicative of the cross-sectional area ofthe lumen) at respective locations within the lumen. For someapplications, the blood velocity data points from the endoluminalimaging device pullback are used to co-register the endoluminal datapoints to respective locations along the lumen within an extraluminalimage (such as an angiogram) of the lumen. For example, the followingtechnique may be used:

It is assumed that flow in the lumen is constant and that the bloodvelocity within the lumen is therefore inversely proportional to thecross-section of the lumen. Cross-sectional areas of the lumen atrespective locations along the lumen are determined, by performing imageprocessing on the extraluminal image of the lumen, e.g., byautomatically performing QCA on the extraluminal image, and/or byperforming densitometry on the extraluminal image. The blood velocitydata points acquired by the endoluminal data-acquisition device arecorrelated with the cross-sectional areas determined from theextraluminal image, such as to determine locations within theextraluminal image that correspond to the location of the endoluminalimaging device at the time of the acquisition of respective endoluminalimages by the endoluminal imaging device.

For example, the pullback of the endoluminal imaging device may commencewhen the endoluminal imaging device is at a known location with respectto the lumen within the extraluminal image. It may be determined, basedupon the blood velocity data, that when the n^(th) endoluminal image wasacquired, the cross-section of the lumen at the location of theendoluminal imaging device was 50 percent of the cross-section of thelumen at the location of the endoluminal imaging device within the lumenwhen pullback commenced. The extraluminal image may then be analyzed todetermine the location within the extraluminal image at which thecross-section of the lumen is 50 percent of the cross-section of thelumen at the location of the endoluminal imaging device when pullbackcommenced. Based upon this analysis, the processor determines thelocation within the extraluminal image that corresponds to the n^(th)endoluminal image. In general, the co-registration functionalitydetermines that a blood velocity data point acquired in temporalproximity to a given endoluminal data point is associated with a givenlocation along the lumen. In response thereto, the co-registrationfunctionality determines that the given endoluminal data point isassociated with the given location along the lumen.

For some applications, techniques described in US 2012/0004537 and/or inInternational Patent Application PCT/IL2013/050438 (published as WO13/175472), both of which application are incorporated herein byreference, are used in conjunction with the above-describedco-registration technique. Typically, an output is generated in responseto the co-registration. For some applications, the endoluminal datapoints include endoluminal images, and, based upon the co-registration,the endoluminal images are arranged in an image stack. Typically, theendoluminal image stack is generated by extracting endoluminal images atlocations along the lumen. From each image, a cross section of the image(typically, one line of pixels) is extracted and placed in the stack ata location corresponding to the determined location of the endoluminalimage along the lumen. Thus, the images are positioned at locationswithin the stack corresponding to relative locations along the lumen atwhich the images were acquired. For some applications, the endoluminaldata points are functional endoluminal data points, and a display of theendoluminal data points is generated, in which the endoluminal datapoints are positioned at locations corresponding to relative locationswithin the lumen at which the endoluminal data points were acquired.Typically, the functional endoluminal data points are displayed in thestack by displaying a stack of indications of the functional endoluminaldata points, locations of the indications within the stack correspondingto relative locations within the lumen at which the endoluminal datapoints were acquired. For example, numerical indications of thefunctional endoluminal data points may be displayed and/orrepresentations of the functional endoluminal data points (which may bebased upon a color legend, for example) may be displayed. For someapplications, indications of non-functional endoluminal data points aredisplayed in the described manner.

For some applications, while observing an extraluminal image of thelumen, one or more locations along the lumen are indicated by a user. Inresponse thereto, based upon the co-registration, previously-acquiredendoluminal data points (e.g., images) corresponding to the one or morelocations are displayed. For some applications, user interface 73 isused to select the one or more locations. Typically, the user designatesa location using the user interface, and, in response thereto, typicallyautomatically and on-line, the system identifies a location along thelumen as corresponding to the designated location, and retrieves anddisplays a corresponding endoluminal data point (e.g., image).

For some applications, data acquired by a first endoluminal modality(e.g., IVUS) are co-registered with the extraluminal image, e.g., inaccordance with the techniques described hereinabove. Subsequently, dataacquired by a second endoluminal modality (e.g., OCT) are co-registeredwith the extraluminal image, e.g., in accordance with the techniquesdescribed hereinabove. Consequently, due to both data sets beingco-registered with the extraluminal image, the two data sets areco-registered to one another. For some applications, the two endoluminaldata sets are displayed overlaid or otherwise merged with one another.

For some applications, movement (e.g., pullback) of the endoluminaldata-acquisition device is performed in the course of a continuousinjection of contrast agent performed under fluoroscopic imaging. Forexample, the endoluminal data-acquisition device may be an OCT probe,which typically requires concurrent flushing of the lumen during imageacquisition, in order to remove blood from the lumen, since the bloodinterferes with the OCT imaging. Therefore, typically, duringendoluminal imaging with an OCT probe, contrast agent is continuouslyinjected into the lumen. As described hereinabove, typically,extraluminal images of the lumen are acquired in the presence ofcontrast agent, in order to determine the cross-sectional area of thelumen (e.g., by performing QCA and/or densitometry on the extraluminalimages). For some applications, a single injection of contrast agent isused (a) to facilitate the acquisition of a set of endoluminal datapoints, and (b) to facilitate determination of the cross-sectional areaof the lumen. For some applications, based upon the determinedcross-sectional area of the lumen, the endoluminal data points areco-registered to the extraluminal image, e.g., using the techniquesdescribed hereinabove.

In general, the scope of the present invention includes non-invasivelydetermining a value of a luminal-flow-related index of the subject at aplurality of locations along the lumen, at least partially by performingimage processing on the two-dimensional angiographic images, inaccordance with the techniques described herein, and co-registering theluminal-flow-related index at the locations to a set of endoluminal datapoints (e.g., endoluminal images, or endoluminal functional datapoints). Typically, while an endoluminal data-acquisition device isbeing moved through the lumen, the device acquires a set of endoluminaldata points of the lumen at a plurality of locations within the lumen.Co-registration functionality 77 of the processor determines thatrespective endoluminal data points correspond to respective locationsalong the lumen, for example using techniques described in US2012/0004537 and/or in International Patent ApplicationPCT/IL2013/050438 (published as WO 13/175472), both of which applicationare incorporated herein by reference. Thus, the co-registrationfunctionality determines that respective endoluminal data pointscorrespond to respective values of the luminal flow-related index.Typically, an output is generated in response to the aforementionedco-registration. For example, an endoluminal image frame may bedisplayed together with an indication of the value of theluminal-flow-related index at the location along the lumen at which theendoluminal image was acquired.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

The invention claimed is:
 1. Apparatus comprising: an image-acquisitiondevice configured to acquire a plurality of angiographic image frames ofa lumen of a subject; and at least one processor configured: to controlthe image-acquisition device to acquire the plurality of angiographicimage frames of the lumen of the subject, to determine an angiographicimage-based fractional flow reserve (FFR) value at a given locationwithin the lumen, wherein the angiographic image-based FFR value isdetermined based only on image processing of the plurality ofangiographic image frames, to compare the first angiographic image-basedFFR value to a first threshold value and a second threshold value, todrive a display in communication with the processor to provide a visualindication of a treatment for the lumen of the subject, in response tothe angiographic image-based FFR value passing the first thresholdvalue, and to drive the display, in response to the angiographicimage-based FFR value passing the second threshold value but not passingthe first threshold value, to provide a visual indication that anintraluminal FFR value be determined in a further procedure using amodality different than the image-acquisition device, wherein thefurther procedure comprises obtaining intraluminal measurements using asensor that is inserted into the lumen.
 2. The apparatus according toclaim 1, wherein the processor is configured to determine theangiographic image-based FFR value by: determining geometry of the lumenat the given location, by analyzing the plurality of angiographic imageframes, determining a time it takes a contrast agent to travel a knowndistance through the lumen, by analyzing the plurality of angiographicimage frames, and determining a value of a current flow-relatedparameter of the lumen based upon the time it takes the contrast agentto travel the known distance through the lumen and the determinedgeometry of the lumen.
 3. The apparatus according to claim 2, wherein:the processor is further configured to receive an indication of a valueof a second flow-related parameter of the subject; and the processor isconfigured to determine the angiographic image-based FFR value bydetermining a relationship between the value of the current flow-relatedparameter and the value of the second flow-related parameter.
 4. Theapparatus according to claim 3, wherein the processor is configured todetermine the angiographic image-based FFR value based upon a determinedblood velocity and geometry of the lumen at the location, using amachine-learning classifier.
 5. The apparatus according to claim 3,wherein the processor is configured to determine the relationshipbetween the value of the current flow-related parameter and the value ofthe second flow-related parameter using a machine-learning classifier.6. The apparatus according to claim 3, wherein the indication of thevalue of the second flow-related parameter of the subject is based on ahistoric angiographic image sequence obtained when the lumen washealthy.
 7. The apparatus according to claim 1, wherein the givenlocation includes a location in a vicinity of a stenosis within thelumen, and wherein the processor is configured to determine theangiographic image-based FFR value by determining the angiographicimage-based FFR value in the vicinity of the stenosis.
 8. The apparatusaccording to claim 1, wherein the processor is configured to determine avalue of instantaneous wave-free ratio of the subject at the locationbased on the plurality of angiographic image frames.
 9. The apparatusaccording to claim 1, wherein the processor is configured to: generate astabilized image stream, by: identifying at least a portion of the lumenin the plurality of angiographic image frames, and aligning theplurality of angiographic image frames with respect to one another suchthat the portion of the lumen in each of the plurality of angiographicimage frames is aligned with the portion of the lumen in the otherangiographic image frames of the plurality of angiographic image frames,and generate, at a location that corresponds to the location and that iswithin the stabilized image stream, an indication of the angiographicimage-based FFR value at the location.
 10. The apparatus according toclaim 1, wherein the processor is configured to generate an indicationof the angiographic image-based FFR value using a color legend, on animage of the lumen.
 11. The apparatus according to claim 1, wherein theprocessor is configured to determine the angiographic image-based FFRvalue by: performing a quantitative coronary angiography (QCA)measurement on at least one image frame of the plurality of angiographicimage frames to determine a cross-sectional area of the lumen at thegiven location; tracking flow of a contrast agent to travel a knowndistance through the lumen; and determine a value of a currentflow-related parameter of the lumen based upon an amount of time ittakes the contrast agent to travel the known distance through the lumenand the determined cross-sectional area of the lumen; and determine thefirst FFR value based on the value of the current flow-related parameterof the lumen.
 12. A method for use with a plurality of angiographicimage frames of a lumen of a subject, the method comprising: acquiringthe plurality of angiographic image frames of a lumen of a subject,using an image-acquisition device; and using at least one processor:controlling, by the at least one processor, the image-acquisition deviceto acquire the plurality of angiographic image frames of the lumen ofthe subject; determining an angiographic image-based fractional flowreserve (FFR) value at a given location within the lumen, based only onimage processing of the plurality of angiographic image frames;comparing the angiographic image-based FFR value to a first thresholdvalue and a second threshold value, driving a display in communicationwith the processor to provide a visual indication of a treatment for thelumen of the subject, in response to the angiographic image-based FFRvalue passing the first threshold value; and driving the display, inresponse to the angiographic image-based FFR value passing the secondthreshold value but not passing the first threshold value, to provide avisual indication that an intraluminal FFR value be determined in afurther procedure using a modality different than the image-acquisitiondevice, wherein the further procedure comprises obtaining intraluminalmeasurements using a sensor that is inserted into the lumen.
 13. Themethod according to claim 12, wherein determining the first angiographicimage-based FFR value comprises: determining geometry of the lumen atthe given location within the lumen, by analyzing the plurality ofangiographic image frames, determining a time it takes a contrast agentto travel a known distance through the lumen, by analyzing the pluralityof angiographic image frames, and determining a value of a currentflow-related parameter of the lumen based upon the time it takes thecontrast agent to travel the known distance through the lumen and thedetermined geometry of the lumen.
 14. The method according to claim 13,further comprising, using the processor receiving an indication of avalue of a second flow-related parameter of the subject, whereindetermining the value of the angiographic image-based FFR value of thesubject at the given location within the lumen comprises determining arelationship between the value of the current flow-related parameter andthe value of the second flow-related parameter.
 15. The method accordingto claim 14, wherein determining the value of the current flow-relatedparameter at the location within the lumen comprises, using amachine-learning classifier, determining the value of the currentflow-related parameter at the location within the lumen, based upon adetermined blood velocity and geometry of the lumen at the location. 16.The method according to claim 14, wherein determining the relationshipbetween the value of the current flow-related parameter and the value ofthe second flow-related parameter comprises determining the relationshipbetween the value of the current flow-related parameter and the value ofthe second flow-related parameter using a machine-learning classifier.17. The method according to claim 12, wherein the given locationincludes a location in a vicinity of a stenosis within the lumen, andwherein determining the angiographic image-based FFR value comprisesdetermining the angiographic image-based FFR value in the vicinity ofthe stenosis.
 18. The method according to claim 12, further comprisingdetermining a value of instantaneous wave-free ratio of the subject atthe location.
 19. The method according to claim 12, further comprising:generating a stabilized image stream, by: identifying at least a portionof the lumen in the plurality of angiographic image frames, and aligningthe plurality of angiographic image frames with respect to one anothersuch that the portion of the lumen in each of the plurality ofangiographic image frames is aligned with the portion of the lumen inthe other angiographic image frames in the plurality of angiographicimage frames; and generating an indication of the angiographicimage-based FFR value on the stabilized image stream.
 20. The methodaccording to claim 12, further comprising generating, on an image of thelumen, an indication of the angiographic image-based FFR value using acolor legend.
 21. Apparatus comprising: an image-acquisition deviceconfigured to acquire a plurality of angiographic image frames of alumen of a subject; and at least one processor configured: to controlthe image-acquisition device to acquire the plurality of angiographicimage frames of the lumen of the subject; to determine an angiographicimage-based fractional flow reserve (FFR) value at a given locationwithin the lumen, wherein the angiographic image-based FFR value iscalculated based only on image processing of angiographic image frames,to compare the angiographic image-based FFR value to a first thresholdvalue and a second threshold value, and to drive a display incommunication with the processor, in response to the angiographicimage-based FFR value passing the second threshold value but not passingthe first threshold value, to provide a visual indication that anintraluminal FFR value be determined in a further procedure using amodality different than the image-acquisition device, wherein thefurther procedure comprises obtaining intraluminal measurements using asensor that is inserted into the lumen.